EP0652893A1 - Kininogenase inhibitors - Google Patents
Kininogenase inhibitorsInfo
- Publication number
- EP0652893A1 EP0652893A1 EP91915557A EP91915557A EP0652893A1 EP 0652893 A1 EP0652893 A1 EP 0652893A1 EP 91915557 A EP91915557 A EP 91915557A EP 91915557 A EP91915557 A EP 91915557A EP 0652893 A1 EP0652893 A1 EP 0652893A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- group
- amino
- phe
- arg
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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-br ⁇ kinin) are potent medic rs of inflammation. Their r .n actions are as follows:
- PCs prostaglandins
- PCs certain actions of kinins, particularly pain and vascular permeability above, are potentiated by PCs, although PCs themselves do not cause pain nor do they induce vascular permeability at the concentrations found in inflamed tissue. PCs 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 ⁇ - ⁇ - ⁇ , of cysteine proteinases such as cathepsins B, H and L, calpaih -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 L-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:-
- FIG. 3 Sequences flanking cleavage site I in human HMWK As shown, 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 allergic inflammation (e.g. asthma and hay fever).
- allergic 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 oedem ⁇ 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, ad inistrability 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- [ _ residue and Y a carbonyl-activating or binding group the structure being:-
- 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) th same or different forming a dipeptide group th amino acid of A optionally carrying a termina group (other than hydrogen) and being any amin or imino-acid residue (but preferably of D configuration) and of B being a lipophili amino-acid residue of D- or L-configuration bu not proline or a proline analogue, or conformational analogue of said dipeptide grou wherein the peptide link is replaced b -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
- the side chain R 1 is that of a basic amino aci or amino acid analogue (preferably of L configuration) and R is H or lower alkyl ( C ⁇ C 4 ) or C ⁇ or the peptide link comprisin -N(R)- is replaced leading to a conformationa mimic as above.
- C ⁇ may be replace by nitrogen.
- cyclohexylalanine, adamantylalanine (not Ala Leu lie 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 j 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:
- Y * groups as given below, first in more general terras and then in terms of more detailed preferences, subject in both cases to the provisos expressed in defining the compounds of the invention earlier.
- the detailed preferences are given in groups under roman numerals, which are also indicated, in brackets, with the first listing which is:-
- R 4 , R D and R° are as below
- R **** alkyl or substituted alkyl including aarryyll oorr aarr ⁇ yl alkyl and -CH 2 R 3 where R 3 fluoroalkyl
- R 9 * -NH as such or alkylated, or amino acyl
- Y -CH - 9
- D nitrogen or carbon and -Dj is a saturated or unsaturated heterocyclic ring or a bicyclic ring system, each is 5 - 8 membered, where there may be other hetero- atoms (N, S, 0) and carbons or nitrogens may optionally be substituted by alkyl, branched alkyl, cycloalkyl, carboxyalkyl, carboxy (attached to carbon), amino, alkoxy, alkoxymethyl or (carbon) as carbonyl or other groups beneficial for interaction with the enzyme.
- 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 , ter: butylglycine .
- R H (when however B is not phenylalanine unless R 8 is carboxylalkyl or derivatized carboxylalkyl) ; or alkyl, branched alkyl (C ⁇ - 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 the same or different but excluding H.
- alkyl (C-. - C 4 ) derivative e.g. cyclohexylalanine but excluding Ala, Leu, lie, Val, Nva, Met, Nle, Phe, Tyr, Trp, Nal(l) and their N-methyl derivatives
- R 9 NH_, N'-alkylamino (where the alkyl groups include branched and/or cycloalkyl
- 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) and isobutyl chloroformate (50.73 mmol) were added at -20°C. After 20 min. this mixture vas added to a solution of diazomethane (0.1 mole) in Et 2 O at -5°C. After 2 hours the diazoketone . 12 was isolated as a yellow solid.
- Boc-Phg-OH (19.9 mmol) was dissolved in AcOH/H 2 0 (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 4_i (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, rhinenchy ⁇ is, and external skin treatment.
- the suitable dosage is 1 to 1000 mg/day/person.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909019558A GB9019558D0 (en) | 1990-09-07 | 1990-09-07 | Enzyme inhibitors |
GB9019558 | 1990-09-07 | ||
PCT/GB1991/001479 WO1992004371A1 (en) | 1990-09-07 | 1991-09-02 | Kininogenase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0652893A1 true EP0652893A1 (en) | 1995-05-17 |
Family
ID=10681831
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91915557A Withdrawn EP0652893A1 (en) | 1990-09-07 | 1991-09-02 | Kininogenase inhibitors |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0652893A1 (fi) |
JP (1) | JPH06501461A (fi) |
AU (1) | AU8438791A (fi) |
CA (1) | CA2090858A1 (fi) |
FI (1) | FI930946A (fi) |
GB (1) | GB9019558D0 (fi) |
HU (1) | HUT64084A (fi) |
IE (1) | IE913120A1 (fi) |
MC (1) | MC2313A1 (fi) |
NO (1) | NO930731L (fi) |
PT (1) | PT98885A (fi) |
WO (1) | WO1992004371A1 (fi) |
ZA (1) | ZA917096B (fi) |
Families Citing this family (61)
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SE9103612D0 (sv) * | 1991-12-04 | 1991-12-04 | Astra Ab | New peptide derivatives |
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US6984627B1 (en) | 1993-06-03 | 2006-01-10 | Astrazeneca Ab | Peptide derivatives |
SE9301911D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptide derivatives |
US5783563A (en) * | 1993-06-03 | 1998-07-21 | Astra Aktiebolag | Method for treatment or prophylaxis of venous thrombosis |
SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
GB9318637D0 (en) * | 1993-09-08 | 1993-10-27 | Ferring Res Ltd | Enzyme inhibitors |
US5486623A (en) | 1993-12-08 | 1996-01-23 | Prototek, Inc. | Cysteine protease inhibitors containing heterocyclic leaving groups |
SE9404196D0 (sv) * | 1994-12-02 | 1994-12-02 | Astra Ab | New antithrombotic formulation |
US6025472A (en) * | 1994-12-21 | 2000-02-15 | Corvas International, Inc. | N-substituted glycine derivatives as enzyme inhibitors |
US5696231A (en) * | 1994-12-21 | 1997-12-09 | Corvas International, Inc. | N-substituted glycine derivatives as enzyme inhibitors |
US6586466B2 (en) | 1995-10-30 | 2003-07-01 | Smithkline Beecham Corporation | Carbohydrazide-protease inhibitors |
SK56798A3 (en) | 1995-10-30 | 1998-12-02 | Smithkline Beecham Corp | Protease inhibitors, pharmaceutical composition containing them and their use |
TW541316B (en) * | 1995-12-21 | 2003-07-11 | Astrazeneca Ab | Prodrugs of thrombin inhibitors |
IL139162A0 (en) | 1998-04-24 | 2001-11-25 | Dimensional Pharm Inc | Amidinohydrazone, alkoxyguanidine and aminoguanidine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
YU42401A (sh) | 1998-12-14 | 2003-12-31 | Ortho-Mcneil Pharmaceuticals Inc. | Supstituisani heterociklični acil-tripeptidi korisni kao modulatori receptora trombina |
US20030144175A1 (en) | 1998-12-23 | 2003-07-31 | Smithkline Beecham Corporation | Protease inhibitors |
EP1158996A4 (en) | 1999-02-18 | 2005-01-12 | Kaken Pharma Co Ltd | NEW AMID DERIVATIVES AS GROWTH HORMONE SECRETION CONVEYORS |
WO2001034599A1 (en) | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
JP2003513972A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害剤 |
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
EA005893B1 (ru) | 2000-03-21 | 2005-06-30 | Смитклайн Бичам Корпорейшн | Ингибиторы протеаз |
GB0205527D0 (en) * | 2002-03-08 | 2002-04-24 | Ferring Bv | Inhibitors |
CA2491611A1 (en) | 2002-07-03 | 2004-01-15 | Bio Science International, Inc. | Peptides comprising aromatic d-amino acids and methods of use |
FR2846969A1 (fr) * | 2002-11-08 | 2004-05-14 | Salles Jean Pierre | Nouveaux vecteurs moleculaires amphiphiles fluorocarbones a usage biomedical et medical |
EP1736465A4 (en) * | 2004-03-31 | 2009-06-17 | Ajinomoto Kk | ANILINE DERIVATIVES |
GB0918922D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminopyridine derivatives |
GB0918924D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Azaindole derivatives |
GB0918923D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminothiazole derivatives |
GB2494851A (en) | 2011-07-07 | 2013-03-27 | Kalvista Pharmaceuticals Ltd | Plasma kallikrein inhibitors |
GB201212081D0 (en) | 2012-07-06 | 2012-08-22 | Kalvista Pharmaceuticals Ltd | New polymorph |
IL239682B (en) | 2013-01-08 | 2018-10-31 | Kalvista Pharmaceuticals Ltd | History of benzylamine and 2-(aminomethyl)pyridine |
GB201300304D0 (en) | 2013-01-08 | 2013-02-20 | Kalvista Pharmaceuticals Ltd | Benzylamine derivatives |
GB2510407A (en) | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
MX363689B (es) | 2013-05-23 | 2019-03-29 | Kalvista Pharmaceuticals Ltd | Derivados de heterociclicos. |
MX366498B (es) | 2013-08-14 | 2019-07-11 | Kalvista Pharmaceuticals Ltd | Inhibidores de calicreina plasmatica. |
GB2517908A (en) | 2013-08-14 | 2015-03-11 | Kalvista Pharmaceuticals Ltd | Bicyclic inhibitors |
TWI636047B (zh) | 2013-08-14 | 2018-09-21 | 英商卡爾維斯塔製藥有限公司 | 雜環衍生物 |
EP3204352B1 (en) | 2014-10-06 | 2020-07-01 | Cortexyme, Inc. | Inhibitors of lysine gingipain |
GB201421085D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
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CA3004095A1 (en) | 2015-11-09 | 2017-05-18 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
RU2020140891A (ru) | 2016-05-31 | 2021-02-10 | Калвиста Фармасьютикалз Лимитед | Производные пиразола в качестве ингибиторов калликреина |
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GB201609603D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-[(6-cyano-2-fluoro-3-methoxyphenyl)Methyl]-3-(methoxymethyl)-1-({4-[(2-ox opyridin-1-YL)Methyl]phenyl}methyl)pyrazole-4-carboxamide |
WO2018053353A1 (en) | 2016-09-16 | 2018-03-22 | Cortexyme, Inc. | Ketone inhibitors of lysine gingipain |
CN107043338B (zh) * | 2017-03-24 | 2018-09-25 | 东华大学 | 一类5-氨基酮戊酸衍生物及其制备方法和应用 |
CN107011217B (zh) * | 2017-03-24 | 2018-08-14 | 东华大学 | 一类脂溶性5-氨基酮戊酸衍生物及其制备方法和应用 |
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CN114206852A (zh) | 2019-08-09 | 2022-03-18 | 卡尔维斯塔制药有限公司 | 血浆激肽释放酶抑制剂 |
GB201918994D0 (en) | 2019-12-20 | 2020-02-05 | Kalvista Pharmaceuticals Ltd | Treatments of diabetic macular edema and impaired visual acuity |
GB2591730A (en) | 2019-12-09 | 2021-08-11 | Kalvista Pharmaceuticals Ltd | New polymorphs |
TW202228686A (zh) | 2020-10-15 | 2022-08-01 | 英商卡爾維斯塔製藥有限公司 | 血管性水腫之治療 |
EP4232031A1 (en) | 2020-10-23 | 2023-08-30 | Kalvista Pharmaceuticals Limited | Treatments of angioedema |
WO2022172006A1 (en) | 2021-02-09 | 2022-08-18 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
WO2023002219A1 (en) | 2021-07-23 | 2023-01-26 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
EP4288036A1 (en) | 2022-04-27 | 2023-12-13 | Kalvista Pharmaceuticals Limited | Formulations of a plasma kallikrein inhibitor |
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EP0009010B1 (en) * | 1978-07-18 | 1983-03-02 | Kabi AB | Bradykinin inhibiting tripeptide derivatives, process for their preparation and pharmaceutical preparations containing them |
US4563305A (en) * | 1981-01-07 | 1986-01-07 | University Of Miami | Radiolabelled substrates for assaying mammalian enzymes |
US4835253A (en) * | 1987-04-03 | 1989-05-30 | The University Hospital | Specific inhibitors of tissue kallikrein |
ZA897514B (en) * | 1988-10-07 | 1990-06-27 | Merrell Dow Pharma | Novel peptidase inhibitors |
-
1990
- 1990-09-07 GB GB909019558A patent/GB9019558D0/en active Pending
-
1991
- 1991-09-02 CA CA002090858A patent/CA2090858A1/en not_active Abandoned
- 1991-09-02 EP EP91915557A patent/EP0652893A1/en not_active Withdrawn
- 1991-09-02 AU AU84387/91A patent/AU8438791A/en not_active Abandoned
- 1991-09-02 JP JP3514802A patent/JPH06501461A/ja active Pending
- 1991-09-02 WO PCT/GB1991/001479 patent/WO1992004371A1/en not_active Application Discontinuation
- 1991-09-02 HU HU93610A patent/HUT64084A/hu unknown
- 1991-09-02 MC MC912313D patent/MC2313A1/xx unknown
- 1991-09-05 IE IE312091A patent/IE913120A1/en unknown
- 1991-09-06 PT PT98885A patent/PT98885A/pt not_active Application Discontinuation
- 1991-09-06 ZA ZA917096A patent/ZA917096B/xx unknown
-
1993
- 1993-02-26 NO NO93930731A patent/NO930731L/no unknown
- 1993-03-03 FI FI930946A patent/FI930946A/fi unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9204371A1 * |
Also Published As
Publication number | Publication date |
---|---|
GB9019558D0 (en) | 1990-10-24 |
NO930731L (no) | 1993-05-07 |
FI930946A0 (fi) | 1993-03-03 |
CA2090858A1 (en) | 1992-03-08 |
PT98885A (pt) | 1992-08-31 |
MC2313A1 (fr) | 1993-09-27 |
AU8438791A (en) | 1992-03-30 |
IE913120A1 (en) | 1992-03-11 |
ZA917096B (en) | 1992-04-29 |
HU9300610D0 (en) | 1993-05-28 |
HUT64084A (en) | 1993-11-29 |
WO1992004371A1 (en) | 1992-03-19 |
FI930946A (fi) | 1993-04-26 |
NO930731D0 (no) | 1993-02-26 |
JPH06501461A (ja) | 1994-02-17 |
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