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WO2006004841A2 - Agonistes de galanine - Google Patents

Agonistes de galanine Download PDF

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Publication number
WO2006004841A2
WO2006004841A2 PCT/US2005/023122 US2005023122W WO2006004841A2 WO 2006004841 A2 WO2006004841 A2 WO 2006004841A2 US 2005023122 W US2005023122 W US 2005023122W WO 2006004841 A2 WO2006004841 A2 WO 2006004841A2
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compound
alkyl
group
substituted
groups
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PCT/US2005/023122
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WO2006004841A3 (fr
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Tamas Bartfai
Susana Conde Ceide
Gebhard Haberhauer
Laszlo Somogyi
Julius Rubek, Jr.
Laurent Trembleau
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to agonists of galanin. More specifically, the invention relates to the development of molecular libraries having agonist activity with respect to the peptide hormone galanin and to the identification and synthesis of individual bioactive molecules within such libraries.
  • Galanin a 29-30 amino acids-long neuropeptide, has been shown to affect feeding, cognitive, sexual behavior, and regulates seizure and pain thresholds when applied intraventricularly (M. E. Vrontakis, Curr. Drug Target CNS Neurol. Disord., (2002) 1, 531-541 ; A. Mazarati, et al., Neuroscientist, (2001) 7, 506-517; and T. Bartfai, et al., Crit. Rev. Neurobiol., (1993) 7, 229- 274). Galanin actions are mediated through three GPCR type receptors present in the brain and the peripheral nervous system (T. A. Branchek, et al., Trends Pharmacol.
  • Galanin binds to at least three different G-protein coupled receptors (GaIRI -3) and influences such processes as insulin secretion, gut secretion/motility, memory, sexual behavior, and pain regulation among others.
  • GaIRI -3 G-protein coupled receptors
  • Transgenic mice overexpressing galanin have much higher seizure thresholds (M. Kokaia, et al., Proc. Natl. Acad. ScL U. S.
  • Galnon ( Figure 1 ) is a non-peptide galanin receptor ligand that was designed to display analogs of the three major pharmacophores of galanin: (Trp 2 , Asn 5 , Tyr 9 ) on a linear, peptide-like backbone (A. Jureus, et al., J. Pept. Res., (1997) 49, 195-200; and T. Land, et al., Brain Res., (1991) 558, 245- 250).
  • Galnon is a low affinity, non-receptor subtype selective agonist that acts at both GaIRI and GalR2 type receptors (K. Saar, et al., Proc. Natl. Acad. Sci. U. S.
  • the pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries.
  • the present disclosure uses the tripeptidomimetic, galnon, and displays its presumed pharmacophores on a rigid molecular scaffold.
  • the scaffold is related to marine natural products and presents three functional groups near one another in space, in the manner reminiscent of a protein surface.
  • Galmic like galanin, suppresses long-term synaptic plasticity (LTP) in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered intraperitoneally.
  • LTP synaptic plasticity
  • Galmic applied intraperitonaly shows antidepressant-like effects in the forced swim test and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection.
  • One aspect of the invention is directed to a compound represented by the following structure:
  • YR 1 , YR 2 , and YR 3 may each optionally and independently form an amino radical of naturally occurring or non-naturally occurring amino acid;
  • R 7 is a radical independently selected, at each occurrence, from the group consisting of -H, C 1-6 alkyl, substituted C 1-6 alkyl, (C 0 . 4 alkyl)-(C 6 . 14 aryl), substituted (C 0 . 4 alkyl)-(C 6 .
  • alkyl and aryl groups are optionally substituted with up to 3 substituents selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NO 2 , -OH, -COOH, -CONH 2 , -NH 2 , -SH, C 1-4 alkyl, C 1-4 oxyalkyl, -C(O)(O-C 1-4 alkyl), C 1-4 aminoalkyl, C 1-4 thioalkyl, W(C 1-4 alkyl)silyl.
  • the presumed pharmacophore of galnon or analog thereof may be more narrowly defined so that YR 1 , YR 2 , and YR 3 are each independently selected from the group of consisting of radicals represented by the following
  • -YR 1 , -YR 2 , and -YR 3 are each -OR 1 , -OR 2 , and -OR 3 , respectively. More particularly, -YR 1 , -YR 2 , and -YR 3 are each independently C 1-6 alkoxy, substituted C 1-6 alkoxy, -O-(C 0 . 4 alkyl)-(C 6 . 14 aryl), or substituted -O-(C 0 . 4 alkyl)-(C 6 _ 14 aryl), subject to the above proviso.
  • YR 1 , YR 2 , and YR 3 are each -NHR 1 , -NHR 2 , and -NHR 3 , respectively.
  • Preferred examples include the following structures:
  • the second aspect of the invention is directed to a chemical intermediate employable for synthesizing compounds of the above first aspect of the invention.
  • the chemical intermediate is represented by the following structure:
  • X is a diradical independently selected at each occurrence from the group consisting of -O- and -S-;
  • Z is a radical independently selected at each occurrence from the group consisting of -H, C 1-6 alkyl, C 2 . 6 alkenyl, and C 2-6 alkynyl;
  • R 4 , R s and R 6 are each independently C,_ 6 alkyl, optionally substituted with 1-3 of -F, -Cl, -Br, -I, -OH, C 1-4 alkoxy, -NH 2 , C 1-4 aminoalkyl, C 2 . 4 aminodialkyl, -SH, C 1-4 thioalkyl, or oxo; and
  • n 0-5.
  • a third aspect of the invention is directed to a method of making a compound of claim 1.
  • a compound of formula I is reacted with H 2 in the presence of a suitable catalyst, followed by reaction with R 1 NH 2 in the presence of a coupling reagent to yield a compound of formula II.
  • the compound of formula I is represented as follows:
  • X, Z, n, R 4 , R 5 ,and R 6 are each as defined in the compound that comprises the first aspect of the invention.
  • PG 1 , PG 2 and PG 3 are orthogonal protecting groups.
  • the preferred orthogonal protecting groups are the protecting groups employed in the chemical intermediate that comprises the second aspect of the invention, viz., PG 1 is benzyl, PG 2 is trimethylsilylethyl, and PG 3 is methyl.
  • R 1 of R 1 NH 2 is the same as defined in the first aspect of the invention.
  • the compound of formula Il is represented as follows:
  • the compound of formula Il is reacted with a fluoride source, followed by reaction with R 2 NH 2 in the presence of a coupling agent, wherein R 2 is as defined in the first aspect of the invention, to yield a compound of formula III:
  • Another aspect of the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the first aspect of the invention or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the invention is directed to a method for treating a mammal having a condition mediated by a galanin deficiency comprising administering to the mammal in need thereof the composition of the pharmaceutical composition described in the previous aspect of the invention.
  • the mammal is suffering from at least one condition selected from the group consisting of Alzheimer's disease, depression, epilepsy, and an eating disorder.
  • Figure 1 illustrates the structures of Galnon and of various platform structures that present C 3 symmetry, viz. Dendroamide C, a prior art synthetic scaffold (1), and Galmic.
  • Figure 2 illustrates a synthetic method for producing Galmic.
  • Figure 3 illustrates a representation of the calculated molecular structure of Galmic.
  • Figure 4 illustrates a chart for presenting the effects of Galmic on long-term synaptic plasticity in mouse dentate gyrus (DG) slices.
  • Figure 5 illustrates a bar chart for presenting the anti-seizure activity of Galmic.
  • Figure 6 illustrates a graph and a bar chart representing the effects of
  • Figure 7 illustrates a bar chart for presenting the results of open field and force swim tests for Galmic.
  • Figure 8 illustrates a table comparing the affinity of Galmic and galnon for galanin receptors.
  • Figure 9 illustrates a procedure for synthesizing oxazole derivatives (18a and 18b) employable for making macrocycles such as compound 1 and Galmic.
  • Figure 10 illustrates a procedure for linking three oxazole derivatives (18a and 18b) to form a linear intermediate (21).
  • Figure 11 illustrates a procedure for cyclizing the linear intermediate (21) to form a macrocycle having three oxazoles linked by trans amide bonds (11).
  • Figure 12 illustrates a procedure for derivatizing the cyclic intermediate (11 ) for producing Galmic (2) or a generic form of the invention (12).
  • Figure 13 illustrates an alternative method for cyclizing a linear intermediate (3a or 3b) to form a macrocycle having three oxazoles linked to one another with trans amide bonds, each of the linking amide bonds having an asymmetric carbon, each asymmetric carbon having a differentially protected ester (6a or 6b).
  • the present disclosure describes the synthesis and characterization of a library of triamides having galanin receptor agonist activity.
  • the library of triamides was derived from the coupling of amines to the triacid ( Figure 2).
  • the library was screened and one agonist of particular activity was identified as being a systemically active, subtype-selective agonist of galanin receptor.
  • the agonist is herein given the name of Galmic.
  • Galmic represents a second generation peptide ligand mimic that, through its interactions with galanin receptors, exhibits galanin agonist-like effects in a variety of animal models upon systemic administration.
  • Galmic employs a platform that was inspired by a number of biologically active and peptide-derived marine natural products such as Dendroamide C (D. Faulkner, J. Nat. Prod. Rep., (1999) 16, 155; G. R. Pettit, Pure Appl. Chem., (1994) 66, 2271 ; M. G. Garson, Chem. Rev., (1993) 93, 1699; B. S. Davidson, Chem. Rev., (1993) 93, 1771 ; and N. Fuesetani, et al., Chem. Rev., (1993) 93, 1793), macrocycles that contain three oxazole or thiazole rings linked by trans amide bonds (G.
  • the molecule is a platform that can present three functional groups on the same face. It serves as core structure for solution phase combinatorial chemistry.
  • the present disclosure describes the structure of Galmic ( Figure 1 ).
  • Galmic Despite its high molecular weight (Mw 984), Galmic penetrates the blood brain barrier reasonably quickly as evidenced by its effects in suppressing status epilepticus after intraperitonal injection of a 2 mg/kg i.p. dose (Figure 5C). Under conditions of intrahippocampal administration, Galmic was 6-7 fold more potent than Galnon (K. Saar, et al., Proc. Natl. Acad. ScL U. S. A., (2002) 99, 7136-7141) in inhibiting SSSE. Similarly, systemically administered Galmic has potent behavioral effects in the forced swim test where it exhibits antidepressant like activity at 15 mg/kg i.p. dose ( Figure 6).
  • Galmic a 10 '5 M or higher concentration must be achieved in the brain to exert the observed effects in seizure and behavioral models ( Figure 5, 6 and 7) used here.
  • Figure 8 a 10 '5 M or higher concentration must be achieved in the brain to exert the observed effects in seizure and behavioral models ( Figure 5, 6 and 7) used here.
  • Galmic reported here are congruent with the action of a galanin type 1 receptor agonist and occur at similar doses as those of galnon (2-20 mg/kg i.p.), the tripeptide mimetic (K. Saar, et al., Proc. Natl. Acad. ScL U. S. A., (2002) 99, 7136-7141 ).
  • Secondary amides such as peptides are regarded as liabilities in transport across membranes because their hydration, particularly at the N-H bonds, resists partitioning into hydrophobic environments.
  • the activity of Galmic compound in vivo was, therefore, unexpected as it requires transport across membranes including the blood/brain barrier.
  • the secondary amides that are part of the macrocyclic framework are internally solvated since, at best, a single water molecule can be accommodated in the center of the structure.
  • the amides that attach the side chains to the periphery of the scaffold are also capable of internal solvation: the NH donors of the peripheral amides are hindered to external water but can find their complements internally in the N and O acceptors of the oxazole subunits through rotations around the bonds indicated.
  • Galmic for galanin receptors was determined by competitive equilibrium binding experiments using membranes prepared from GaIRI or GalR2 expressing cells. Galmic displaces [ 125 l]-galanin binding in
  • the components of the chemical library were tested as competitors at concentrations 10 "8 -10 "4 M.
  • the radioligand binding assay was performed in 150 ⁇ l_ binding buffer [50 mM Tris-CI (pH 7.4), 5 mM MgCI 2 , 0.05 % (w/v) bovine serum albumin, supplemented with peptidase and protease inhibitors: 50 ⁇ M leupeptin, 100 ⁇ M phenylmethanesulfonyl fluoride and 2 ⁇ g/mL aprotinin]. Incubations were carried out at room temperature for 45 min and terminated by rapid vacuum filtration through glass fiber filters (Packard, Meriden, CT, USA).
  • Galmic similar to galanin (1-29), blocked the late-phase of LTP treated slices and on average (21 - 61 min post-LTP induction) caused a 30% ⁇ 1 (Galmic) reduction in the fEPSP slope compared to DMSO treated slices (t-test: p ⁇ 0.005).
  • the hippocampal slices were prepared from male C57BI/6 mice (4-6 weeks old).
  • a glass micropipette (1-5 M ⁇ ) filled with ACSF or NaCI was placed in the outer one-third of the molecular layer (OML) of the inner blade of the dentate gyrus (DG), and a bipolar tungsten stimulating electrode was placed in the apex of the DG to activate the lateral perforant pathway innervating OML.
  • the field potentials were recorded by an AxoClamp 2B (Axon Instrument), digitized and processed using a Digidata and pCLAMP acquisition software (Axon Instrument), respectively.
  • the stability of the fEPSP was established by recording fEPSP responses stimulated at 40-50% of maximum intensity (one/min for 15 min).
  • the input-output curve was generated by stimulating the pathway at three different intensities (threshold, half-maximal and maximally effective).
  • the baseline fEPSP recording was conducted 15 min prior to and 60 min after LTP induction at 40-50% of the maximal amplitude response.
  • LTP was induced by two (20 sec intervals) trains of high frequency stimulus (HFTs) at 100 Hz for 1 sec at maximally effective stimulus intensity.
  • HFTs high frequency stimulus
  • SSSE was induced in adult male Wistar rats as previously described (A. M. Mazarati, et al., J. Neurosci., (1998) 18, 10070-10077). Briefly, animals were subjected to 30-minutes perforant path stimulation (PPS) through a stimulating electrode, which had been chronically implanted into the angular bundle of perforant path, using a Grass stimulator model 8800 with the following parameters: 10 s of 20 Hz trains of 1 ms 30 V pulses delivered every min, together with the continuous 2 Hz stimulation using the same parameters.
  • PPS perforant path stimulation
  • Electrographic activity was acquired through a recording electrode-guide cannula (Plastics One, Roanoke, VA), which had been chronically implanted into the dentate gyrus ipsilateral to PPS, and analyzed off-line using Harmonie Software (Stellate Systems, Montreal, Quebec) configured for automatic detection and saving of seizures and spikes.
  • SSSE duration i.e. the time between the end of PPS and the occurrence of the last seizure
  • time in seizures i.e. cumulative time spent in software-recognized seizures during SSSE
  • total number of seizure episodes spike duration, i.e. time of the occurrence of the last electrographic spike.
  • Galmic was dissolved in 50% v/v DMSO and was administered into the dentate gyrus using an injection cannula connected to a Hamilton microsyringe and placed into the lumen of the guide cannula.
  • Galmic was injected during either induction phase of SSSE, 10 min after the end of PPS, or during drug-resistant maintenance phase (C. G. Wasterlain, et al., Epilepsia, (2000) 41 Suppl 6, S134-143), 60 min after the end of PPS.
  • Control animals were treated with the vehicle (DMSO). Each group included 4-5 animals.
  • animals received i.p. injections of Galmic, 10 min after PPS (3 animals per group). Data were analyzed using one-way ANOVA, with Bonferroni post-hoc test.
  • mice After an injection of 20 ⁇ l of 2.5 % formalin into the paw, mice displayed two phases of flinching behavior. Phase 1 started with initial intense flinches occurring 1 - 2 min post-injection, followed by a rapid decline at 5 - 6 min. Phase 2 began after 15 - 20 min with the maximal response typically observed around 25 - 30 min after the formalin injection (Figure 6). Injection of Galmic to mice (2.45 - 9.8 ⁇ moles/kg) produced a dose-dependent inhibition on both Phase 1 and 2 ( Figure 6). The ED 50 value ( ⁇ moles/kg, 95% C.I.) of inhibitory effects of Galmic on Phase 1 was 2.9 (2.1-4.1 ) and Phase 2 was 3.7 (2.6-5.2).
  • mice Male C57BI/6 mice (25-3Og, Harlan Sprague Dawley, Indianapolis, IN) were used.
  • an automated sensing system was employed (T. L. Yaksh, et al., J. Appl. Physiol., (2001) 90, 2386-2402). Briefly, a C-shape soft metal band (4.8mm wide and 8.5mm long, 0.1g) was placed on one of the hind paws of an animal. After acclimation for 30 min, animals were gently restrained and 20 ⁇ l of 2.5% formalin solution was injected subcutaneously into the dorsal surface of the banded paw with a 30-gauge needle.
  • Figure 9 illustrates the synthesis of oxazole containing precursors to compounds of the invention.
  • the amino malonate 13 is transesterified with an alkali oxide such as PG 1 OLi and then reacted under the conditions shown with a hydroxy amino acid derivative such as Boc-serine or Boc-threonine methyl ester (R 4 and Z are as defined herein) to give the amide.
  • an alkali oxide such as PG 1 OLi
  • R 4 and Z are as defined herein
  • the latter compound may be cyclized to the oxazoline by exposure to Burgess' Reagent and converted to oxazole by treatment with NiO 2 in a suitable solvent such as benzene, toluene and the like. A second transesterification may be carried out to give the orthogonally protected compound 15.
  • a variety of oxazole building blocks may be prepared by slight modification of these techniques.
  • the oxidation with NiO 2 may be omitted and the oxazoline transesterified to give analogous oxazoline building blocks.
  • Oxazole and oxazoline precursors to compounds of the invention may readily be prepared by slight modification of procedures described in copending U.S. Application No. 09/053,837, hereby incorporated by reference in its entirety.
  • the acyclic precursor to compounds of the invention may be assembled by iterative procedures well known in the art of peptide synthesis.
  • 18a may be Boc-deprotected with, e.g. TFA or another suitable acid, and coupled to carboxyl-deprotected 18b (i.e., PG 2 was previously removed) in the presence of a base such as DlEA using typical peptide coupling reagents such as HBTU or PYBOP.
  • the resulting dimer 20 may be Boc-deprotected again and coupled to a third component as shown to give compound 21.
  • R 1 , R 2 , and R 3 moieties may be installed on the building blocks by selective deprotection of the appropriate carboxylic acid and coupling by any of the methods described above.
  • the building blocks are then linked by coupling reactions as before.
  • suitable protecting groups may be used on the amino and carboxyl groups in the synthesis of the linear precursor so long as an orthogonal protection scheme is maintained.
  • Macrocyclization of the linear precursor may be effected by a variety of methods well known in the art.
  • coupling agents such as EDCI or PYBOP may be used under typical conditions (i.e., in the presence of a base such as DIEA and a suitable solvent such as DMF) to form an amide bond between the amino- and carboxyl-containing termini of the acyclic precursor in moderate yield.
  • the coupling agent DEPBT is used according to Li, H., et al., Organic Letters 1 , 91-93 (1999).
  • Figure 13 illustrates another preferred method of macrocyclization where the R 1 , R 2 , and R 3 moieties are either amides or orthogonally protected esters or a combination of both.
  • an activated ester 4 is formed from the free terminal carboxyl using, e.g., pentafluorophenol and DCC in a suitable solvent such as EtOAC.
  • the amino protecting group e.g., Boc
  • a suitable acid such as trifluoroacetic acid
  • Heating the latter compound with DMAP in a solvent such as toluene yields the macrocycle 6.
  • Figure 12 exemplifies a method for installation of R 1 , R 2 , and R 3 amides from an orthogonally protected macrocycle of the invention.
  • a first protecting group such as benzyl ester may be removed by hydrogenolysis in a suitable solvent in the presence of a suitable catalyst such as Pd on carbon and the like.
  • the amide is formed from the free carboxyl and an amine (R 1 NH 2 ) by use of typical peptide coupling reagents such as those described herein or others well known in the art.
  • a second protecting group e.g.
  • Example 1 Synthesis of Compounds of the Invention General Considerations: Reactions were performed under N 2 atmosphere. NMR spectra were recorded on Varian 300 and Bruker DRX 600 spectrometers. Chemical shifts are given in ppm relative to TMS. The spectra were referenced to deuterated solvents indicated in brackets in the analytical data. Thin Layer Chromatography (TLC) were performed on aluminium sheets of silica gel. Purification by column chromatography were performed on silicagel 60 (230-400 mesh; Merck KgaA). Solvents and chemicals were used as purchased from commercial suppliers.
  • TLC Thin Layer Chromatography
  • Macrocycle 6a was prepared using the same procedure in 70% yield.
  • Carboxylic acid 7a was prepared using the same procedure in 71% yield (120 mg).
  • Triamid 8a(i) was prepared using the same procedure in 82% yield (105 mg).
  • Characteristics of 8b(i) MALDI-FTMS [M+Na] + : expected: 1111.4859; observed: 1111.4831. Characteristics of 8a(i): MALDI-FTMS [M+Naf: expected: 1111.4859; observed: 1111.4843
  • Triamid 8a(i ⁇ ) was prepared using the same procedure in quantitative yield (107 mg).
  • ACOH stands for acetic acid.
  • Bn stands for benzyl
  • Boc stands for t-butyloxycarbonyl.
  • DCC stands for N.N-dicyclohexylcarbodiimide.
  • DCM stands for dichloromethane
  • DEPBT stands for 3-(diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3/-/)-one.
  • DIEA stands for N-ethyl-N,N-diisopropylamine, also known as Hunig's base.
  • DMAP stands for 4-d ⁇ methylaminopyridine.
  • DMF stands for dimethylformamide.
  • DMPU stands for 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1/-/)-pyrimidinone.
  • DPPA diphenylphosphine azide
  • EDCI stands for 1-ethyl-3-(3-(dimethylaminopropyl) carbodiimide.
  • E t OAC stands for ethyl acetate.
  • HOBt stands for 1 -hydroxybenzotriazole.
  • PYBOP stands for benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
  • THF stands for tetrahydrofuran.
  • protecting groups with respect to hydroxyl groups, amine groups, carboxyl groups, and sulfhydryl groups refers to chemical moieties that are attached to and protect these functionalities from undesirable reaction during chemical syntheses.
  • Protecting groups are well known to those skilled in the art and include those set forth in Protective Groups in Organic
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, f-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; carbamates such as /-butyl carbamate (Boc), fluorenylmethyl carbamate (Fmoc), and benzyl carbamate (Cbz); and others.
  • amides such as, formamide, acetamide, trifluoroacetamide, and benzamide
  • imides such as phthalimide, and dithiosuccinimide
  • carbamates such as /-butyl carbamate (Boc), fluorenylmethyl carbamate (Fmoc), and benzyl carbamate (Cbz); and others.
  • protected sulfhydryl groups include, but are not limited to, thioethers such as S-f-butyl thioether, S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • protected carboxyl groups include but are not limited to esters such as methyl, ethyl, f-butyl, trimethylsilylethyl, benzyl, and the like.
  • a "pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • salts of basic amino acids the instant invention includes, for example, arginine, lysine and ornithine.
  • Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • alkyl refers to unsubstituted alkyl groups that do not contain heteroatoms.
  • the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the term also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3> -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH
  • the term also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • the term also includes polycyclic alkyl groups such as, but not limited to, adamantyl, norbomyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound.
  • Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms, and more preferred such groups have from 1 to 10 carbon atoms. Even more preferred such groups, also known as lower alkyl groups, have from 1 to 5 carbon atoms.
  • Most preferred alkyl groups include straight and branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and -CH(CH 3 ) 2 .
  • substituted alkyl refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom in halides such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxy!
  • a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups
  • a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines
  • a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups.
  • Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms.
  • One example of a substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group.
  • alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, aryloxy group, or heterocyclyloxy group.
  • Still other alkyl groups include alkyl groups that have an amine, alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine group.
  • aryl refers to unsubstituted aryl groups that do not contain heteroatoms.
  • the term includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • aryl includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below.
  • a preferred aryl group is phenyl.
  • Aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
  • substituted aryl group has the same meaning with respect to aryl groups that substituted alkyl groups had with respect to alkyl groups.
  • a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein.
  • substituted alkenyl has the same meaning with respect to alkenyl groups that substituted alkyl groups had with respect to alkyl groups.
  • a substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • Preferred substituted alkenyl groups have form 2 to 20 carbons, and more preferred such groups have from 2 to 10 carbons.
  • alkynyl refers to straight and branched chain groups such as those described with respect to alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to -C(C(H), -C(C(CH 3 ), -C(C(CH 2 CH 3 ), -C(H 2 )C(C(H), -C(H) 2 C(C(CH 3 ), and -C(H) 2 C(C(CH 2 CH 3 ) among others.
  • Preferred alkynyl groups have form 2 to 20 carbons, and more preferred such groups have from 2 to 10 carbons.
  • substituted alkynyl has the same meaning with respect to alkynyl groups that substituted alkyl groups had with respect to alkyl groups.
  • a substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • aralkyl refers to alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group as defined above.
  • methyl (-CH 3 ) is an alkyl group.
  • a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the carbon of the methyl were bonded to a carbon of benzene, then the compound is an aralkyl group (i.e., a benzyl group).
  • the term includes, but is not limited to, groups such as benzyl, diphenylmethyl, and 1-phenylethyl (-CH(C 6 H 5 )(CH 3 )) among others.
  • substituted aralkyl has the same meaning with respect to aralkyl groups that substituted aryl groups had with respect to aryl groups.
  • a substituted aralkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon or a non-hydrogen atom.
  • heterocyclyl refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • heterocyclyl includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members; compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups.
  • heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 member rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 member rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 member rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazplyl, isoxazolyl, oxadiazolyl (e.g.
  • saturated 3 to 8 member rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g.
  • unsaturated 3 to 8 member rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • saturated 3 to 8 member rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 member rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.
  • Heterocyclyl groups also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1 ,1 -dioxide.
  • Preferred heterocyclyl groups contain 5 or 6 ring members.
  • More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, pyridine homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
  • substituted heterocyclyl refers to a heterocyclyl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups.
  • examples include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1 -methyl piperazinyl, 2-phenoxy-thiophene, and 2-chloropyridinyI among others.
  • substituted heterocyclyl groups also include heterocyclyl groups in which the bond to the non-hyrogen atom is a bond to a carbon atom that is part of a substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, or unsubstituted heterocyclyl group.
  • Examples include but are not limited to 1-benzylpiperdinyl, 3-phenythiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and 4-(piperidin-1-yl)-piperidinyl.
  • heterocyclylalkyl refers to alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above.
  • methyl (-CH 3 ) is an alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is a heterocyclylalkyl group.
  • substituted heterocyclylalkyl has the same meaning with respect to heterocyclylalkyl groups that substituted aralkyl groups had with respect to aralkyl groups.
  • a substituted heterocyclylalkyl group also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group.
  • a substituted heterocyclylalkyl group also includes groups in which a carbon bond or a hydrogen bond of the alkyl part of the group is replaced by a bond to a substituted and unsubstituted aryl or substituted and unsubstituted arylalkyl group. Examples include but are not limited to phenyl-(piperidin-1-yl)-methyl and phenyl-(morpholin-4-yl)-methyl.
  • alkoxy refers to a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group as defined above.
  • substituted alkoxy refers to a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an otherwise substituted alkyl group as defined above.
  • a "pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • salts of basic amino acids the instant invention includes, for example, arginine, lysine and ornithine.
  • Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • ketones are typically in equilibrium with their enol forms.
  • ketones and their enols are referred to as tautomers of each other.
  • tautomers of each other As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds having formulas I and Il are within the scope of the present invention.
  • Compounds of the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.
  • Figure 1 illustrates the structures of Galnon and of various platform structures that present C 3 symmetry, viz. Dendroamide C, a prior art synthetic scaffold (1), and Galmic.
  • Galnon is a prior art agonist of galanin receptor
  • Dendroamide C is a biologically active peptide-derived marine natural product having a macrocycle that contains three oxazole or thiazole rings linked by trans amide bonds
  • scaffold (1) is the prior art scaffold upon which Galmic was constructed
  • Galmic is a novel agonist of galanin receptor.
  • Figure 2 illustrates a synthetic method for producing a library of potential galanin agonists and for fractionating the library to obtain GalGalmic.
  • R 1 , R 2 , and R 3 represent random substituents resulting from the condensation of amines a, b, and c.
  • EDCI stands for 1 -ethyl-3-(3- (dimethylaminopropyl) carbodiimide
  • HOBt stands for 1-hydroxybenzotriazole
  • DIEA stands for N-ethyl-N,N-diisopropyIamine, also known as Hunig's base
  • DMF stands for dimethylformamide
  • TFA stands for trifluoroacetate
  • Boc stands for t-butyloxycarbonyl.
  • Figure 3 illustrates a representation of the calculated structure of Galmic: the side chain amides have been arbitrarily rotated to show the most compact structure. In any conformation the side chains appear on the same face of the macrocycle.
  • Figure 4 illustrates a chart for presenting the effects of Galmic on long-term synaptic plasticity in mouse dentate gyrus (DG) slices.
  • Galmic (1 ⁇ M) for 10-15 min prior to LTP-induction attenuated the early and late phases of LTP compared to the DMSO (0.03%v/v) treated slices.
  • the bar illustrates the duration of the vehicle (DMSO) or drug administration and the arrow indicates the time of stimulation with high frequency trains (tetanus).
  • the effect of Galmic was significantly different from DMSO- treated slices at 2-6 min and 17-60 min post-LTP induction.
  • Galmic (1 ⁇ M) caused a similar effect as administration of galanin (1-29) (1 ⁇ M) in attenuating the LTP in DG. All values are mean ⁇ SEM (t-test: ** P ⁇ 0.005).
  • Figure 5 illustrates a bar chart for presenting effects of Galmic on self-sustaining status epilepticus (SSSE).
  • Galmic was injected into the dentate gyrus ipsilateral to the stimulation site at 10 min (A) or 60 min (B) after PPS. Dose (nanomoles) is indicated in the legend next to the graph.
  • C Intraperitoneal administration of Galmic 10 min after PPS attenuated SSSE at 2mg/kg i.p., but not 1 mg/kg i.p.. Asterisk- p ⁇ 0.05 vs Control (One-Way ANOVA + Bonferroni t-test).
  • Figure 6 illustrates a graph and a bar chart representing the effects of Galmic on formalin induced flinching
  • the bars represent the total number of flinches in each phase: Ph-I (1-9 min), Ph-Il (10-60 min), Ph-IIA (10-40 min) and Ph-IIB (41-60 min).
  • the data are expressed as mean ⁇ s.e.m. *p ⁇ 0.05 vs. the vehicle group, one-way ANOVA followed by Dunnett's tests.
  • Figure 7 illustrates a bar chart for presenting the effects of treatment of rats with Galmic in the forced swim test (left panel). Activity was measured during a 10 min test at 45 min after injection. Galmic (15 mg/kg i.p.) produced a significant increase in activity in the test, compared to vehicle treated (DMSO 50 % v/v) animals, consistent an antidepressant-like profile. Right panel, Galmic (15 mg/kg i.p.) was administered in the open field test. Galmic significantly reduced the locomotor activity in this task compared to vehicle treated animals, without any obvious signs of sedation. Values represent group means (( SEM) (independent means f-test: * p ⁇ 0.01 vs control).
  • Figure 8 illustrates a table comparing the affinity of Galmic and galnon for galanin receptors. Ki values of Galmic and Galnon at GaIRI and GalR2 receptors were determined by displacement of [ 125 I] galanin from membranes prepared from human Bowes' cells (hGalRI ) and stably transferred CHO cells expressing rat GalR2, respectively. [ 125 I] galanin concentration was 0.2 nM, and Galmic and galnon concentrations were between 10 "8 M - 10 "4 M. Ki values were calculated with Prism software.
  • Figure 9 illustrates a procedure for synthesizing oxazole derivatives (18a and 18b) employable for making macrocycles such as compound 1 and Galmic.
  • R 4 is a substituent that corresponds to the methyl groups attached to the asymmetric carbons of Galmic. When R 4 is methyl, R 4 serves to prevent racemization of Galmic. Larger alkyl groups and substituents other than methyl may also be employed to prevent racemization. If racemization is unimportant, R 4 may be hydrogen.
  • Figure 10 illustrates a procedure for linking three oxazole derivatives (18a and 18b) to form a linear intermediate having three asymmetric carbons, each asymmetric carbon having a differentially protected ester (21).
  • Figure 11 illustrates a procedure for cyclizing the linear intermediate (21) to form a macrocycle having three oxazoles linked by trans amide bonds (11).
  • Figure 12 illustrates a procedure for derivatizing the cyclic intermediate
  • R 1 NH 2 , R 2 NH 2 , and R 3 NH 2 correspond to the amines indicated in Figure 2.
  • R 1 NH 2 , R 2 NH 2 , and R 3 NH 2 correspond to the amines indicated in Figure 2 and to a broader range of amines.
  • Figure 13 illustrates an alternative method for cyclizing a linear intermediate (3a or 3b) to form a macrocycle having three oxazoles linked to one another with trans amide bonds, each of the linking amide bonds having an asymmetric carbon, each asymmetric carbon having a differentially protected ester (6a or 6b).
  • Figure 13 further illustrates the conversion of the macrocycle (6a or 6b) to form a Galmic intermediate having a lysine substituent at one of the asymmetric carbons, while the two remaining asymmetric carbons remain differentially protected (8a(ii) or Sb( ⁇ i)).

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Abstract

Galmic, agoniste de récepteur de galanine non peptidique, a un effet sur des comportements dans une crise, lors d'une douleur et dans des tests de la nage forcée.
PCT/US2005/023122 2004-06-29 2005-06-29 Agonistes de galanine WO2006004841A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582673B2 (en) 2004-10-21 2009-09-01 High Point Pharmaceuticals, Llc Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use
EP3364967A2 (fr) * 2015-10-23 2018-08-29 Vifor (International) AG Inhibiteurs de la ferroportine
WO2018174078A1 (fr) * 2017-03-21 2018-09-27 富士フイルム株式会社 Composé peptide ainsi que procédé de fabrication de celui-ci, composition pour criblage, et procédé de sélection de composé peptide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407136B1 (en) * 1999-05-21 2002-06-18 Ortho-Mcneil Pharmaceutical, Inc. 1,4-dithiin and 1,4-dithiepin-1,1,4,4, tetroxide derivatives useful as antagonists of the human galanin receptor
SE0101856D0 (sv) * 2001-05-25 2001-05-25 Uelo Langel Galanin receptor agonist

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7582673B2 (en) 2004-10-21 2009-09-01 High Point Pharmaceuticals, Llc Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use
EP3364967A2 (fr) * 2015-10-23 2018-08-29 Vifor (International) AG Inhibiteurs de la ferroportine
WO2018174078A1 (fr) * 2017-03-21 2018-09-27 富士フイルム株式会社 Composé peptide ainsi que procédé de fabrication de celui-ci, composition pour criblage, et procédé de sélection de composé peptide
RU2731211C1 (ru) * 2017-03-21 2020-08-31 Фуджифилм Корпорэйшн Пептидное соединение и способ его получения, композиция для скринингового использования и способ отбора пептидного соединения
US11319347B2 (en) 2017-03-21 2022-05-03 Fujifilm Corporation Peptide compound and method for producing same, composition for screening use, and method for selecting peptide compound

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