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WO1992004371A1 - Inhibiteurs de la kininogenase - Google Patents

Inhibiteurs de la kininogenase Download PDF

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Publication number
WO1992004371A1
WO1992004371A1 PCT/GB1991/001479 GB9101479W WO9204371A1 WO 1992004371 A1 WO1992004371 A1 WO 1992004371A1 GB 9101479 W GB9101479 W GB 9101479W WO 9204371 A1 WO9204371 A1 WO 9204371A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
amino
mmol
acid
Prior art date
Application number
PCT/GB1991/001479
Other languages
English (en)
Inventor
Michael Szelke
David Michael Evans
David Michael Jones
Original Assignee
Ferring Peptide Research Partnership Kb
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ferring Peptide Research Partnership Kb filed Critical Ferring Peptide Research Partnership Kb
Priority to JP3514802A priority Critical patent/JPH06501461A/ja
Priority to EP91915557A priority patent/EP0652893A1/fr
Priority to CA002090858A priority patent/CA2090858A1/fr
Publication of WO1992004371A1 publication Critical patent/WO1992004371A1/fr
Priority to NO93930731A priority patent/NO930731L/no
Priority to FI930946A priority patent/FI930946A7/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10

Definitions

  • the invention relates to enzyme inhibition and to treatment of disease.
  • Kinins are natural vasoactive peptides liberated in the body from high molecular weight precursors (kininogens) by the action of selective proteases known as kininogenases.
  • the kinins (bradykinin, kallidin and Met-Lys-bra kinin) are potent medi rs of inflammation. Their actions are:
  • PG's certain actions of kinins, particularly pain and vascular permeability above, are potentiated by PG's, although PG's themselves do not cause pain nor do they induce vascular permeability at the concentrations found in inflamed tissue. PG's therefore act as either mediators or potentiators of kinins.
  • the kininogenases are serine proteinases, that is to say proteinases in which the hydroxy group of a serine residue is the nucleophile involved in forming the substrate transition state. They liberate the kinins (bradykinin, kallidin) from the kininogens by limited proteolysis.
  • kininogenase There are several kinds of kininogenase:-
  • Tissue kallikrein also called glandular kallikrein GT or urinary kallikrein UK
  • TK Tissue kallikrein
  • LMWK low molecular weight kininogen
  • KD kinin kallidin
  • the kininogens which are the natural substrates for the kininogenases (they act also as potent inhibitors, Ki approx. 10 - 11 , of cysteine proteinases such as cathepsins B, H and L, calpain and papain) occur in two types: (a) Low molecular weight kininogen (LMWK) with molecular weight in the range 50,000 - 70,000 depending on species of origin and degree of glycosylation.
  • LMWK Low molecular weight kininogen
  • HMWK High molecular weight kininogen
  • H-chain N- terminal or heavy chain
  • L-chain the first twelve amino acids of the C-terminal or light chain
  • cleavage of human HMWK by plasma kallikrein is for example shown schematically in Fig. 1, with details of the sequence at the cleavage sites in Fig. 2 and a more detailed sequence in Fig. 3 where the conventional numbering of residues adajcent to a cleavage site is shown for cleavage site I.
  • the H- and L-Chains are held together by a single disulphide bridge:-
  • plasma kallikrein and tissue kallikrein act at a single site to free the kinin C-terminal site, cleaving between residues 389 and 390, but at sites one residue apart, either side of residue 380, to free the N-terminal of bradykinin (by PK) or kallidin (by TK).
  • PK and HMWK as clotting factors in the intrinsic cascade does not involve the enzymatic release of kinins. However many of the effects of PK and all those of TK do involve such release, being mediated by the kinins released from the respective substrates HMWK and LMWK through selective proteolysis.
  • kininogenase inhibitors are inflammatory conditions, particularly aller g i c inflammation ( e . g . asthma and hay fever ) .
  • aller g i c inflammation e . g . asthma and hay fever .
  • a fuller list of indications is given below:
  • Allergic inflammation e.g. asthma, rhino-conjunctivitis [hay fever], rhinorrhoea, urticaria
  • Inflammation e.g. arthritis, pancreatitis, gastritis, inflammatory bowel disease, thermal injury, crush injury, conjunctivitis
  • Hypotension e.g. shock due to haemorrhage, septicaemia or anaphylaxis, carcinoid syndrome, dumping syndrome
  • Oedema e.g. burns, brain trauma, angioneurotic oedema whether or not as a result of treatment with inhibitors of angiotensin converting enzyme
  • Pain and irritation e.g. burns, wounds, cuts, rashes, stings, insect bites
  • the invention provides a method of treatment (including prophylactic treatment) of an inflammatory or other condition set out in the indications above, particularly, an allergic inflammatory condition, wherein an effective amount of a peptide or peptide-analogue kininogenase inhibitor is administered topically or systemically to a patient suffering from or at risk of the condition. It is believed that for optimum activity, administrability and stability in the body the compounds should not exceed the size of a hexapeptide, that is to say should not comprise more than six amino acid or amino acid analogue residues; the presence of further residues, particularly in a pro-drug from which residues are cleaved in the body to give the compound primarily exerting the desired effect, is however not excluded.
  • the invention provides a method of treatment of the allergic inflammatory phase of asthma, wherein an effective amount of a kininogenase inhibitor such as a mast cell tryptase inhibitor is administered topically or systemically to a patient suffering from or at risk of the condition.
  • a kininogenase inhibitor such as a mast cell tryptase inhibitor
  • the invention extends further to a method of preparation of a medicament for the topical or systemic treatment (including prophylactic treatment) of conditions as above particularly for allergic inflammatory conditions and especially for asthma as above, wherein a kininogenase inhibitor is associated with a pharmaceutically acceptable diluent or carrier to constitute said medicament.
  • the kininogenase inhibitor is conveniently but not essentially of the novel kind now described in which in another aspect, without limitation to any particular clinical indication, the invention provides synthetic, low molecular weight compounds that selectively inhibit kininogenases and thus block the release of kinins from kininogens.
  • the inhibitors are peptide analogues, desirably (as above) not exceeding the size of a hexapeptide in terms of amino acid or analogue residues, based on the known amino acid sequence of the kininogens at cleavage site I, which analogues have sufficient similarity to the cleavage site sequence to bind to the active site of the kininogenase but are not hydrolysable and therefore remain bound, inactivating the enzyme.
  • the inhibitors are essentially of the structure below, in which A represents the P 3 residue, B the P 2 residue, C the P 1 residue and Y a carbonyl-activating or binding group the structure being:-
  • a - B - C - Y I where A, B and C are amino acyl or amino acyl analogue groups linked by peptide bonds or conformational analogues thereof giving a peptide mimic.
  • Other residues in addition to these essential ones may of course be present, including amino acyl or amino acyl analogue residues.
  • a and B amino acyl (including amino acyl analogue) the same or different forming a dipeptide group the amino acid of A optionally carrying a terminal group (other than hydrogen) and being any amino or imino-acid residue (but preferably of D- configuration) and of B being a lipophilic amino-acid residue of D- or L-configuration but not proline or a proline analogue, or a conformational analogue of said dipeptide group wherein the peptide link is replaced by -CH 2 -NH- ('reduced'), -CH(OH)-CH 2 - ('hydroxy'), -CO-CH 2 - ('keto'), -CH 2 -CH 2 - ('hydrocarbon') or other conformational mimic of the peptide link and in:- 0
  • R 1 is that of a basic amino acid or amino acid analogue (preferably of L- configuration) and R is H or lower alkyl ( C 1 - C 4 ) or C ⁇ or the peptide link comprising -N(R)- is replaced leading to a conformational mimic as above.
  • C ⁇ may be replaced by nitrogen.
  • Y a binding enhancing or carbonyl activating group for example selected from H (but only if A or B is cyclohexylalanine, preferably D if at A or L if at B) or alkyl ( C 1 - C 20 ) or fluoroalkyl (C 2 - C 12 ); substituted
  • substituted amino but when the resulting compound is a secondary alkylamide B must not be phenyl-alanine); an amino-acid group or its ester or amide; a carboxylic secondary amide or primary amide, when B must be a bulky lipophilic, non-aromatic amino-acid e.g.
  • cyclohexylalanine (not Ala Leu lle Val Nva Met Nle Phe Tyr Trp Nal (1)); tertiary-carboxamide; carboxy-alkyl group or its ester or amide.
  • substituents are suitably common functional groups that increase binding affinity to the enzyme and/or improve pharmacological properties.
  • a dipeptide mimic is a structure containing non-natural amino acid (amino acid analogue) residues or which is non-peptidic and which in I holds the side-chains of A and B or B and C or all of them in a conformation similar to that present in the parent peptide when bound to the active site of the enzyme. It may also contain features favourable for other interactions with the enzyme, e.g. hydrogen bonding.
  • a mimic may be chosen from the published work on such analogues.
  • Preferred residues for A are imino-acids, (e.g. D-proline or an analogue of proline e.g. pipecolinic acid, azetidine carboxylic acid etc.); lipophilic amino acids (e.g. DPhe, DCha, DChg); strongly basic amino acids (e.g. D-Arg or a guanidinophenylalanine) and for B they are L-Phe, L-Cha, L- ⁇ Nal, L-Tal, L-(4F)Phe L-(NMe)Phe or other substituted phenylalanines.
  • imino-acids e.g. D-proline or an analogue of proline e.g. pipecolinic acid, azetidine carboxylic acid etc.
  • lipophilic amino acids e.g. DPhe, DCha, DChg
  • strongly basic amino acids e.g. D-Arg or a guanidinophenylalanine
  • a and B may also be the N-alkyl (C 1 -C 4 ) or C ⁇ -alkyl ( C 1 -C 7 e.g. methyl, benzyl) analogues of these amino acids.
  • Suitable terminal groups for A include lower alkyl (preferred) or acyl (not excluding amino acyl), alkyl sulphonyl (straight chain or branched or cyclic), amino-alkyl, carboxy alkyl, hydroxy alkyl or any other common protecting group encountered in peptide chemistry.
  • Groups suitable as group Y are specific to the present invention in that they are part of the structure giving the required binding to the active site and are not merely non- interfering end groups. They form a binding group which increases affinity to the enzyme and/or a group which activates the adjacent carbonyl by rendering it more electrophilic. Specific groups are included in the following formula:
  • R 2 , R 4 and R 5 are as below 4
  • R 9 -NH 2 as such or alkylated, or amino acyl
  • R 6 hydrogen lower alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, amino-alkyl, alkylaminocarbonyl.
  • Y an amino-acid residue or any amide (secondary or tertiary) or ester of that residue, L or D configuration.
  • Preferred residues are of lipophilic amino-acids e.g. norleucine, cyclohexylalanine, homocyclohexylalanine, cyclohexylglycine, tert butylglycine.
  • R 7 H (when however B is not phenylalanine unless R 8 is carboxylalkyl or derivatized carboxylalkyl); or alkyl, branched alkyl (C 1 - C 12 ) , cycloalkyl (C 1 -C 20 ) carboxyalkyl or bis (carboxyl) alkyl, which may be derivatized at the carboxyl group to form an amide e.g. with an amino-acid (preferred is arginine) or a substituted amine; N'-dialkylamino; N'-alkylamino-;
  • R 8 R 7 the same or different but excluding H.
  • N'-alkylamino (where the alkyl groups include branched and/or cycloalkyl); an amino-acid residue.
  • Boc-Arg(Z 2 )OH (9.23 mmol) and N-methylmorpholine (11.08 mmol) in dry THF (25 cm 3 ) at -20°C After 20 mins the solid was filtered off and the filtrate added to a solution of sodium borohydride (10.3 mmol) in water (10 cm 3 ) at 0°C After 3 hours 0.3 M KHSO 4 was added, the crude product extracted with EtOAc and purified by flash chromatography on silica with EtOAc - petrol (4:6). The alcohol 1 was isolated as a white solid (97%).
  • N-methylmorpholine 50.85 mmol
  • isobutyl chloroformate 50.73 mmol
  • this mixture vas added to a solution of diazomethane (0.1 mole) in Et 2 O at -5°C.
  • the diazoketone 12 was isolated as a yellow solid.
  • Boc-Phg-OH (19.9 mmol) was dissolved in AcOH/H 2 O (9:1, 100 cm 3 ) and hydrogenated over Rh/C at 60 p.s.i. for 3 days. The catalyst was filtered off and the solvent removed to give Boc-Chg-OH 41 (100%).
  • the present enzyme inhibitor can be formulated by any conventional method in pharmaceutics.
  • the present enzyme inhibitor may be applied in any conventional manner including intravenous injection, intramuscular injection, instillation, oral administration, respiratory inhalation, instillation, rhinenchysis, and external skin treatment.
  • the suitable dosage is 1 to 1000 mg/day/person.

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Abstract

Inhibiteurs de la kininogénase, n'excédant pas au mieux la taille d'un hexapeptide, de la formule (II) dans laquelle A et B représentent un aminoacyle (y compris un analogue d'aminoacyle), celui-ci ou un autre formant un groupe dipeptide, l'acide aminé de A portant un groupe terminal et étant un reste d'un acide iminé ou aminé quelconque (mais de préférence de configuration D) et celui de B étant un reste d'acide aminé lipophilique de configuration D ou L, mais non pas la proline ou un analogue de la proline, ou une formation analogue dudit groupe dipeptide, dans laquelle le maillon peptide est remplacé par -CH2-NH ('réduit'), -CH(OH)-CH2- ('hydroxy'), CO-CH2- ('céto'), CH2-CH2- ('hydrocarbone') ou toute autre formation mimétique de la liaison peptide et dans (III) la chaîne latérale R1 est celle d'un acide aminé de base ou d'un analogue d'acide aminé (de préférence de configuration L) et R est H ou un alkyle inférieur (C¿1?-C4) ou C?α¿ ou la liaison peptide comprenant -N(R)- est remplacée pour donner une formation similaire à celle décrite ci-dessus; Y représente un groupe renforçateur de liaison ou un groupe activateur carbonyle, de préférence sélectionné dans H (lorsque A et B doivent être cyclohexylalanine, de préférence D si à A ou L si à B) ou alkyle (C¿1?-C20) ou fluoroalkyle (C2-C12); oxyméthylène substitué; thiométhylène; sulfoxyméthylène; sulfonyméthylène; aminométhylène; hydrazinométhylène CH2-Het (où Het = un hétérocycle substitué ou non); un amino substitué (mais lorsque le composé ainsi obtenu est un alkylamide secondaire, B ne doit pas être phénylalanine); un groupe aminoacide ou son ester ou amide; un amide primaire ou un amide secondaire carboxylique, lorsque B doit être cyclohexylalanine ou adamantylalanine ou tout autre acide aminé non aromatique, lipophile massif (non pas Ala Leu Ile Val Nva Met Nle Phe Tyr Trp Nal (1)); un carboxamide tertiaire; un groupe carboxy-alkyle ou son ester ou amide ou dérivé aminoacyle.
PCT/GB1991/001479 1990-09-07 1991-09-02 Inhibiteurs de la kininogenase WO1992004371A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP3514802A JPH06501461A (ja) 1990-09-07 1991-09-02 キニノゲナーゼ阻害剤
EP91915557A EP0652893A1 (fr) 1990-09-07 1991-09-02 Inhibiteurs de la kininogenase
CA002090858A CA2090858A1 (fr) 1990-09-07 1991-09-02 Inhibiteurs de la kininogenase
NO93930731A NO930731L (no) 1990-09-07 1993-02-26 Kininogenaseinhibitorer
FI930946A FI930946A7 (fi) 1990-09-07 1993-03-03 Kininogenasinhibitorer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909019558A GB9019558D0 (en) 1990-09-07 1990-09-07 Enzyme inhibitors
GB9019558.7 1990-09-07

Publications (1)

Publication Number Publication Date
WO1992004371A1 true WO1992004371A1 (fr) 1992-03-19

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Application Number Title Priority Date Filing Date
PCT/GB1991/001479 WO1992004371A1 (fr) 1990-09-07 1991-09-02 Inhibiteurs de la kininogenase

Country Status (13)

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EP (1) EP0652893A1 (fr)
JP (1) JPH06501461A (fr)
AU (1) AU8438791A (fr)
CA (1) CA2090858A1 (fr)
FI (1) FI930946A7 (fr)
GB (1) GB9019558D0 (fr)
HU (1) HUT64084A (fr)
IE (1) IE913120A1 (fr)
MC (1) MC2313A1 (fr)
NO (1) NO930731L (fr)
PT (1) PT98885A (fr)
WO (1) WO1992004371A1 (fr)
ZA (1) ZA917096B (fr)

Cited By (62)

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WO1994029335A1 (fr) * 1993-06-03 1994-12-22 Astra Aktiebolag Nouveaux derives peptidiques
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LT3768B (en) 1993-06-03 1996-03-25 Astra Ab Novel peptides derivatives, process for their preparation, pharmaceutical compositions and use starting materials in synthesis of a serine protease inhibitors
WO1996019493A1 (fr) * 1994-12-21 1996-06-27 Corvas International, Inc. DERIVES N-SUBSTITUES DE LA GLYCINE COMME INHIBITEURS DU FACTEUR Xa
US5614499A (en) * 1991-12-04 1997-03-25 Astra Aktiebolag Peptide derivatives as thrombin inhibitors
US5696231A (en) * 1994-12-21 1997-12-09 Corvas International, Inc. N-substituted glycine derivatives as enzyme inhibitors
US5780631A (en) * 1993-06-03 1998-07-14 Astra Aktiebolag Starting materials in the synthesis of thrombin and kininogenase inhibitors
US5795896A (en) * 1994-12-02 1998-08-18 Astra Aktiebolag Antithrombotic formulation, process for its manufacturing, and use thereof
US5965692A (en) * 1995-12-21 1999-10-12 Astra Ab Prodrugs of thrombin inhibitors
US5998470A (en) * 1995-10-30 1999-12-07 Smithkline Beecham Corporation Protease inhibitors
US6096712A (en) * 1993-09-08 2000-08-01 Feering B.V. Kininogen inhibitors
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US6417161B1 (en) 1998-04-24 2002-07-09 3-Dimensional Pharmaceuticals, Inc. Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
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US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
FR2846969A1 (fr) * 2002-11-08 2004-05-14 Salles Jean Pierre Nouveaux vecteurs moleculaires amphiphiles fluorocarbones a usage biomedical et medical
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US6984627B1 (en) 1993-06-03 2006-01-10 Astrazeneca Ab Peptide derivatives
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US7655602B2 (en) 2002-07-03 2010-02-02 Bio Science International, Inc. Peptides comprising aromatic D-amino acids and methods of use
KR100974633B1 (ko) * 2002-03-08 2010-08-06 밴티아 리미티드 칼리크레인의 선택적 디펩타이드 억제제
US7879863B2 (en) 2004-03-31 2011-02-01 Ajinomoto Co., Inc. Aniline derivatives
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WO2011051673A1 (fr) 2009-10-28 2011-05-05 Vantia Limited Dérivés aminothiazole utiles comme inhibiteurs de la klk1
WO2013005045A1 (fr) 2011-07-07 2013-01-10 Kalvista Pharmaceuticals Limited Dérivés de benzylamine en tant qu'inhibiteurs de kallikréine du plasma
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WO2016083816A1 (fr) 2014-11-27 2016-06-02 Kalvista Pharmaceuticals Limited Dérivés de n-((hétéroarylméthyl)-hétéroaryl-carboxamide utilisés en tant qu'inhibiteurs de la kallikréine plasmatique
US9533987B2 (en) 2013-05-23 2017-01-03 Kalvista Pharmaceuticals Limited Heterocyclic derivates
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US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US9834513B2 (en) 2013-01-08 2017-12-05 Kalvista Pharmceuticals Limited Benzylamine derivatives
US9849100B2 (en) 2013-01-09 2017-12-26 Kalvista Pharmaceuticals Limited Pharmaceutical compositions suitable for parenteral administration comprising aqueous suspensions of benzylamine derivatives having low solubilities
US10221161B2 (en) 2013-08-14 2019-03-05 Kalvista Pharmaceuticals Limited Inhibitors of plasma kallikrein
US10364238B2 (en) 2014-11-27 2019-07-30 Kalvista Pharmaceuticals Limited N-((het) arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors
US10730826B2 (en) 2016-09-16 2020-08-04 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US10752607B2 (en) 2016-06-01 2020-08-25 Kalvista Pharmaceuticals Limited Polymorphs of N-[(6-cyano-2-fluoro)-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as kallikrein inhibitors
US10781181B2 (en) 2014-11-27 2020-09-22 Kalvista Pharmaceuticals Limited N-((het) arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors
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FI930946A7 (fi) 1993-04-26
CA2090858A1 (fr) 1992-03-08
JPH06501461A (ja) 1994-02-17
IE913120A1 (en) 1992-03-11
AU8438791A (en) 1992-03-30
FI930946A0 (fi) 1993-03-03
HU9300610D0 (en) 1993-05-28
GB9019558D0 (en) 1990-10-24
EP0652893A1 (fr) 1995-05-17
ZA917096B (en) 1992-04-29
NO930731L (no) 1993-05-07
NO930731D0 (no) 1993-02-26
HUT64084A (en) 1993-11-29

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