US2003027819A1PendingUtilityA1
Beta-sheet mimetics and methods relating to the use thereof
Est. expiryAug 5, 2016(expired)· nominal 20-yr term from priority
A61K 31/437C07K 5/1024C07K 5/021C07K 7/06C07K 5/06139A61K 31/43A61K 31/4152C07K 1/047A61K 31/407C07K 5/06191A61K 31/428A61K 31/5025C07K 5/0821A61K 31/4035A61K 31/424A61K 31/4196
55
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Claims
Abstract
β-sheet mimetics and methods relating to the same are disclosed. The β-sheet mimetics have utility as protease and kinase inhibitors, as well as inhibitors of transcription factors and protein-protein binding interactions. Methods of the invention include administration of a β-sheet mimetic, or use of the same for the manufacture of a medicament for treatment of a variety of conditions associated with the targeted protease, kinase, transcription factor and/or protein-protein binding interaction.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for inhibiting a protease, comprising administering to an animal in need thereof an effective amount of a compound having the structure:
and pharmaceutically acceptable salts thereof,
wherein
A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;
B is selected from N and CH;
C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;
D is selected from N and C(R 4 );
E is selected from
F is an optional carbonyl moiety;
R 1 and R 4 are independently selected from amino acid side chain moieties and derivatives thereof;
R 2 and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2 taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;
R 3 is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;
Y and Z represent the remainder of the molecule; and
any two adjacent CH groups of the bicyclic ring may form a double bond.
2 . The method of claim 1 wherein E is
3 . The method of claim 1 wherein E is
4 . The method of claim 1 wherein E is
with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1 substituent.
5 . The method of claim 1 wherein the protease is a serine protease.
6 . The method of claim 5 wherein the serine protease is selected from thrombin, Factor X, Factor IX, Factor VII, Factor XI, urokinase, HCV protease, chymase, tryptase and kallikrein.
7 . The method of claim 5 wherein the serine protease is thrombin.
8 . The method of claim 5 wherein the serine protease is Factor VII
9 . The method of claim 1 wherein the protease is selected from an aspartic, cysteine and metallo protease.
10 . A method for inhibiting a kinase, comprising administering to an animal in need thereof an effective amount of a compound having the structure:
and pharmaceutically acceptable salts thereof,
wherein
A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;
B is selected from N and CH;
C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;
D is selected from N and C(R 4 );
E is selected from
F is an optional carbonyl moiety;
R 1 and R 4 are independently selected from amino acid side chain moieties and derivatives thereof;
R 2 and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2 taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;
R 3 is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;
Y and Z represent the remainder of the molecule; and
any two adjacent CH groups of the bicyclic ring may form a double bond.
11 . The method of claim 10 wherein E is
12 . The method of claim 10 wherein E is
13 . The method of claim 10 wherein E is
with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1 substituent.
14 . The method of claims 10 wherein the kinase is a serine/threonine or tyrosine kinase.
15 . A method for inhibiting a transcription factor, comprising administering to an animal in need thereof an effective amount of a compound having the structure:
and pharmaceutically acceptable salts thereof,
wherein
A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;
B is selected from N and CH;
C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;
D is selected from N and C(R 4 );
E is selected from
F is an optional carbonyl moiety;
R 1 and R 4 are independently selected from amino acid side chain moieties and derivatives thereof;
R 2 and R 2 1 represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2 taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;
R 3 is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;
Y and Z represent the remainder of the molecule; and
any two adjacent CH groups of the bicyclic ring may form a double bond.
16 . The method of claim 15 wherein E is
17 . The method of claim 15 wherein E is
18 . The method of claim 15 wherein E is
with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1 substituent.
19 . The method of claim 15 wherein the ability of the transcription factor to bind DNA is controlled by reduction of a cysteine residue by a cellular oxidoreductase.
20 . The method of claim 15 wherein the transcription factor is selected from NF-κB, AP-1, Myb, GRE, STAT-1 through -6, NFAT, IRF-1 and MAF.
21 . The method of claim 15 wherein the transcription factor is NF-κB.
22 . The method of claim 15 wherein the transcription factor is AP-1.
23 . The method of claim 19 wherein the cellular oxidoreductase is ref-1.
24 . The method of claim 15 wherein the warm-blooded animal has been diagnosed with, or is at risk of developing, a condition selected from Crohn's disease, asthma, rheumatoid arthritis, ischemia-reperfusion injury, GVHD, ALS, Alzheimer's disease, allograft rejection, adult T-cell leukemia, cancer and inflammatory bowel disease.
25 . A method for inhibiting protein-protein binding interactions, comprising administering to an animal in need thereof an effective amount of a compound having the structure:
and pharmaceutically acceptable salts thereof,
wherein
A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;
B is selected from N and CH;
C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;
D is selected from N and C(R 4 );
E is selected from
F is an optional carbonyl moiety;
R 1 and R 4 are independently selected from amino acid side chain moieties and derivatives thereof;
R 2 and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2 taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;
R 3 is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;
Y and Z represent the remainder of the molecule; and
any two adjacent CH groups of the bicyclic ring may form a double bond.
26 . The method of claim 25 wherein E is
27 . The method of claim 25 wherein E is
28 . The method of claim 25 wherein E is
with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1 substituent.
29 . The method of claim 25 wherein the protein-protein binding interaction is between the SH2 domain or the PDZ domain and another protein.Join the waitlist — get patent alerts
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