USRE41287EExpiredUtilityPatentIndex 47
Cyclic agonists and antagonists of C5A receptors and G Protein-coupled receptors
Est. expiryJun 25, 2017(expired)· nominal 20-yr term from priority
A61P 37/06A61P 9/10A61P 29/00A61P 25/00A61P 25/28A61P 19/02A61P 11/00A61P 17/06A61P 1/02C07K 14/472C07K 7/56A61K 38/00C07K 2299/00
47
PatentIndex Score
1
Cited by
44
References
54
Claims
Abstract
The present invention relates to novel cyclic or constrained acyclic compounds which modulate the activity of G protein-coupled receptors and are useful in the treatment of conditions mediated by G protein-coupled receptors, for example, inflammatory conditions.
Claims
exact text as granted — not AI-modified1. A compound, which has antagonist activity against a C5a receptor, has no agonist activity against a C5a receptor, and has the general formula II:
where A is H, alkyl, aryl, NH 2 , NHalkyl, N(alkyl) 2 , NHaryl or NHacyl;
B is an alkyl, aryl, phenyl, benzyl, naphthyl or indole group, or the side chain of a D- or L-amino acid selected from the group consisting of phenylalanine, homophenylalanine, tryptophan, homotryptophan, tyrosine, and homotyrosine;
C is the side chain of D-, L- or homo-amino acid selected from the group consisting of proline, alanine, leucine valine, isoleucine, arginine, histidine, aspartate, glutamate, glutamine, asparagine, lysine, tyrosine, phenylalanine, cyclohexylalanine, norleucine, tryptophan, cysteine and methionine;
D is the side chain of a D- or L-amino acid selected from the group consisting of cyclohexylalanine, homocyclohexylalanine, leucine, norleucine, homoleucine, homonorleucine and tryptophan;
E is the side chain of a D- or L-amino acid selected from the group consisting of tryptophan and homotryptophan;
F is the side chain of a D- or L-amino acid selected from the group consisting of arginine,
homoarginine, lysine and homolysine or is one of the following side-chains
or another mimetic of an arginine side chain,
where
X is NCN, NNO 2 , CHNO 2 or NSO 2 NH 2 ;
n is an integer from 1 to 4, and
R 1 is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph; and
X 1 is —(CH 2 ) n NH— or (CH 2 ) n —S—, —(CH 2 ) 2 O—, —(CH 2 ) 3 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, or —CH 2 COCHRNH—, where R is the side chain of any common or uncommon amino acid, and
where n is an integer of from 1 to 4.
2. The compound according to claim 1 , which is a compound selected from the group consisting SEQ ID NOS: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
3. The compound according to claim 1 , in which n is 2 or 3.
4. The compound according to claim 1 , in which F is one of the following side-chains
or another mimetic of an arginine side chain;
where
X is NCN, NNO 2 , CHNO 2 or NSO 2 NH 2 ;
n is an integer from 1 to 4, and
R 1 is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph;
B is an indole, indole methyl, benzyl, phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of the aromatic group; and
C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine, tryptophan or methionine.
5. The compound according to claim 1 , which has the formula
Ac-Phe-[Lys-Pro-(dCha)-Trp-Arg] or
Ac-Phe-[Orn-Pro-(dCha)-Trp-Arg].
6. The compound according to claim 1 , in which A is L-arginine.
7. The compound according to claim 1 , in which F is a L-amino acid.
8. The compound according to claim 7 , in which F is L-arginine.
9. A composition comprising a compound according to claim 1 , together with a pharmaceutically-acceptable carrier or excipient.
10. The composition according to claim 9 , wherein in the compound of formula II, F is L-arginine.
11. The composition according to claim 9 , wherein the compound of formula II is a compound selected from the group consisting SEQ ID NOS: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
12. The composition according to claim 9 , wherein the compound of formula II has the formula
Ac-Phe-[Lys-Pro-(dCha)-Trp-Arg] or
Ac-Phe-[Orn-Pro-(dCha)-Trp-Arg].
13. The composition according to claim 9 , in which F is L-arginine.
14. The composition of claim 9 , wherein in the compound of formula II, F is a L-amino acid.
15. The compound according to claim 14 , in which R 1 is methyl, ethyl, propyl, or butyl.
16. The composition according to claim 9 , wherein in the compound of formula II
F is one of the following side-chains
or another mimetic of an arginine side chain;
where
X is NCN, NNO 2 , CHNO 2 or NSO 2 NH 2 ;
n is an integer from 1 to 4, and
R 1 is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph;
B is an indole, indole methyl, benzyl, phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of the aromatic group; and
C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine, tryptophan or methionine.
17. The composition according to claim 16 , wherein in the compound of formula II, R 1 is methyl, ethyl, propyl, or butyl.
18. A method of antagonizing the activity of a C5a receptor on a cell, comprising contacting the cell with the compound of claim 1 in an amount sufficient to antagonize the activity of the C5a receptor on the cell.
19. The method according to claim 18 , wherein in the compound of formula II, F is L-arginine.
20. The method according to claim 18 , wherein the compound of formula II is a compound selected from the group consisting SEQ ID NOS: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
21. The method according to claim 18 , wherein the compound of formula II has the formula
Ac-Phe-[Lys-Pro-(dCha)-Trp-Arg] or
Ac-Phe-[Orn-Pro-(dCha)-Trp-Arg].
22. The method according to claim 18 , wherein in the compound of formula II, F is L-arginine.
23. The method of claim 18 , wherein the cell is in a mammal and said contacting comprises administering the compound to said mammal.
24. The method according to claim 18 , wherein in the compound of formula II, F is a L-amino acid.
25. The method of claim 24 , wherein said mammal is a human.
26. The method according to claim 18 , wherein in the compound of formula II
F is one of the following side-chains
or another mimetic of an arginine side chain;
where
X is NCN, NNO 2 , CHNO 2 or NSO 2 NH 2 ;
n is an integer from 1 to 4, and
R 1 is H or an alkyl, aryl, CN, NH 2 , OH, —CO—CH 2 CH 3 , —CO—CH 3 , —CO—CH 2 CH 2 CH 3 , —CO—CH 2 Ph, or —CO-Ph;
B is an indole, indole methyl, benzyl, phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of the aromatic group; and
C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine, tryptophan or methionine.
27. The method according to claim 26 , wherein in the compound of formula II, R 1 is methyl, ethyl, propyl, or butyl.
28. A method of treating inflammatory arthritis mediated by a C5a receptor, comprising the step of administering an effective amount of a compound according to claim 10 to a mammal in need thereof.
29. The method of claim 28 , wherein the mammal is a human.
30. The method of claim 28 , wherein the inflammatory arthritis is rheumatoid arthritis.
31. A method of treating inflammatory arthritis, comprising the step of administering an effective amount of a compound according to claim 1 to a mammal in need thereof.
32. The method of claim 31 , wherein the mammal is a human.
33. The method of claim 31 , wherein the inflammatory arthritis is rheumatoid arthritis.
34. A compound which is an antagonist of the C5a receptor, and has the formula IV:
where A is any common or uncommon, basic, charged amino acid side chain which serves to position a positively charged group in this position;
B is a non-aromatic amino acid, and
C is any common or uncommon, hydrophobic amino acid side chain which serves to position any alkyl, aromatic or other group in this position; and
D is any common or uncommon, aromatic amino acid which serve to position an aromatic side-chain in this position, and has the structure:
where Z is indole, indole methyl, benzyl, benzene, naphthyl, naphthyl methyl, or a derivative thereof; and
R is H or an alkyl, aromatic, acyl or aromatic-acyl group;
E is any amino acid other than tryptophan and homotryptophan, and
F is the side chain of a D- or L-amino acid selected from the group consisting of arginine, homoarginine, lysine and homolysine.
35. A composition comprising a compound according to claim 34 , together with a pharmaceutically acceptable carrier or excipient.
36. A method of agonizing the activity of a C5a receptor on a cell comprising contacting the cell with the compound of claim 34 in an amount sufficient to agonize the C5a receptor on the cell.
37. The method of claim 36 , wherein the cell is in a mammal and said contacting comprises administering the compound to said mammal.
38. The method of claim 31 , wherein the mammal is a human.
39. A method of treating inflammatory arthritis mediated by a C5a receptor, comprising the step of administering an effective amount of a compound according to claim 34 to a mammal in need thereof.
40. The method of claim 39 , wherein the mammal is a human.
41. The method of claim 39 , wherein the inflammatory arthritis is rheumatoid arthritis.
42. A method of treating inflammatory arthritis, comprising the step of administering an effective amount of a compound according to claim 34 to a mammal in need thereof.
43. The method of claim 42 , wherein the mammal is a human.
44. The method of claim 42 , wherein the inflammatory arthritis is rheumatoid arthritis.
45. A compound having the formula
46. A composition comprising the compound of claim 45 , together with a pharmaceutically acceptable carrier or excipient.
47. A method of agonizing the activity of a C5a receptor on a cell comprising contacting the cell with the compound of claim 45 in an amount sufficient to agonize the C5a receptor on the cell.
48. The method of claim 47 , wherein the cell is in a mammal and said contacting comprises administering the compound to said mammal.
49. The method of claim 48 , wherein the mammal is a human.
50. A method of treating inflammatory arthritis, comprising the step of administering an effective amount of a compound according to claim 45 to a mammal in need thereof.
51. The method of claim 50 , wherein the mammal is a human.
52. A method of treating inflammatory arthritis mediated by a C5a receptor, comprising the step of administering an effective amount of a compound according to claim 45 to a mammal in need thereof.
53. The method of claim 52 , wherein the mammal is a human.
54. The method of claim 52 , wherein the inflammatory arthritis is rheumatoid arthritis.Cited by (0)
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