US2010267639A1PendingUtilityA1
Treatment of osteoarthritis
Est. expiryOct 16, 2022(expired)· nominal 20-yr term from priority
A61P 43/00A61P 19/02A61K 38/12
39
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Claims
Abstract
This invention relates to methods of treatment of osteoarthritis, and especially to treatment of this condition with cyclic peptidic and peptidomimetic compounds which have the ability to modulate the activity of G protein-coupled receptors. The compounds preferably act as antagonists of the C5a receptor, and are active against C5a receptors on polymorphonuclear leukocytes and macrophages. Particularly preferred compounds for use in the invention are disclosed.
Claims
exact text as granted — not AI-modified1 . A method of treatment of osteoarthritis, comprising the step of administering an effective amount of an inhibitor of a C5a G protein-coupled receptor to a subject in need of such treatment, in which the inhibitor is a compound which
(a) is an antagonist of a C5a G protein-coupled receptor, (b) has substantially no agonist activity, and (c) is a cyclic peptide or peptidomimetic compound of formula I
where A is H, alkyl, aryl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-aryl, NH-acyl, NH-benzoyl, NHSO 3 , NHSO 2 -alkyl, NHSO 2 -aryl, OH, O-alkyl, or O-aryl;
B is an alkyl, aryl, phenyl, benzyl, naphthyl or indole group, or B is the side chain of phenylalanine or L-phenylglycine;
C is the side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline;
D is the side chain of D-leucine, D-homoleucine, D-cyclohexylalanine, D-homocyclohexylalanine, D-valine, D-norleucine, D-homo-norleucine, D-phenylalanine, D-tetrahydroisoquinoline, D-glutamine, D-glutamate, or D-tyrosine;
E is the side chain of an amino acid selected from the group consisting of L-phenylalanine, L-tryptophan and L-homotryptophan, or is L-1-naphthyl or L-3-benzothienyl alanine;
F is the side chain of L-arginine, L-homoarginine, L-citrulline, or L-canavanine, or a bioisostere thereof; and
X 1 is —(CH 2 ) n NH— or (CH 2 ) n S—, where n is an integer of from 1 to 4; —(CH 2 ) 2 O—; —(CH 2 ) 3 O—; —(CH 2 ) 3 —; —(CH 2 ) 4 —; —CH 2 COCHRNH—; or —CH 2 —CHCOCHRNH—, where R is the side chain of any common or uncommon amino acid.
2 . The method of claim 1 , in which n is 2 or 3.
3 . The method of claim 1 , in which A is an acetamide group, an aminomethyl group, or a substituted or unsubstituted group.
4 . The method of claim 2 , in which A is a substituted, and the substituent is an alkyl chain of 1 to 6 carbon atoms, or a phenyl or toluoyl group.
5 . The method of claim 3 , in which the substituent is an alkyl chain of 1 to 4 carbon atoms.
6 - 9 . (canceled)
10 . The method of claim 1 , in which the inhibitor is a compound which has antagonist activity against C5aR, and has no C5a agonist activity.
11 . The method of claim 1 , in which the inhibitor has potent antagonist activity at sub-micromolar concentrations.
12 . The method of claim 1 , in which the compound has a receptor affinity IC 50 <25 μM, and an antagonist potency IC 50 <1 μM.
13 . The method of claim 1 , in which the compound is selected from the group consisting of compounds 1 to 6, 10 to 15, 17, 19, 20, 22, 25, 26, 28, 30, 31, 33 to 37, 39 to 45, 56 to 58 and 60 to 64 wherein said compounds have chemical structures as follows:
14 . The method of claim 13 , in which the compound is compound 1 (AcF-[OP-DCha-WR]), compound 33 (AcF-[OP-DPhe-WR]), compound 60 (AcF-[OP-DCha-FR]) or compound 45 (AcF-[OP-DCha-WCit]) wherein said compounds have chemical structures as follows:
15 . The method of claim 1 , in which the inhibitor is used in conjunction with one or more other agents for the treatment of osteoarthritis.
16 . The method of claim 1 , wherein A is NH-acyl; B is the side chain of L-phenylalanine; C is the side chain of L-proline; D is the side chain of D-cyclohexylalanine; E is the side chain of L-tryptophan; F is the side chain of L-arginine; and X 1 is —(CH 2 ) n NH—, where n is 3.
17 . A method for treating osteoarthritis in a mammal, said method comprising the step of: administering to a mammal in need thereof, an effective amount of a composition comprising a C5a G protein-coupled receptor antagonist compound that (a) has substantially no agonist activity and (b) is a cyclic peptide or peptidomimetic compound of formula I:
wherein:
A is H, alkyl, aryl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-aryl, NH-acyl, NH-benzoyl, NHSO 3 , NHSO 2 -alkyl, NHSO 2 -aryl, OH, O-alkyl, or O-aryl;
B is an alkyl, aryl, phenyl, benzyl, naphthyl or indole group, or B is the side chain of L-phenylalanine or L-phenylglycine;
C is the side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline;
D is the side chain of D-leucine, D-homoleucine, D-cyclohexylalanine, D-homocyclohexylalanine, D-valine, D-norleucine, D-homo-norleucine, D-phenylalanine, D-tetrahydroisoquinoline, D-glutamine, D-glutamate, or D-tyrosine;
E is the side chain of an amino acid selected from the group consisting of L-phenylalanine, L-tryptophan and L-homotryptophan, or is L-1-naphthyl or L-3-benzothienyl alanine;
F is the side chain of L-arginine, L-homoarginine, L-citrulline, or L-canavanine, or a bioisostere thereof; and
X 1 is —(CH 2 ) n NH— or (CH 2 ) n —S—, where n is an integer of from 1 to 4; —(CH 2 ) 2 O—; —(CH 2 ) 3 O—; —(CH 2 ) 3 —; —(CH 2 ) 4 —; —CH 2 COCHRNH—; or —CH 2 —CHCOCHRNH—, where R is the side chain of any common or uncommon amino acid.
18 . The method of claim 17 , wherein
A is H, alkyl, aryl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-aryl, NH-acyl, NH-benzoyl, NHSO 3 , NHSO 2 -alkyl, NHSO 2 -aryl, OH, O-alkyl, or O-aryl; B is an alkyl, aryl, phenyl, benzyl, naphthyl or indole group, or B is the side chain of L-phenylalanine or L-phenylglycine; C is the side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline; D is the side chain of D-leucine, D-homoleucine, D-cyclohexylalanine, D-homocyclohexylalanine, D-valine, D-norleucine, D-homo-norleucine, D-phenylalanine, D-tetrahydroisoquinoline, D-glutamine, D-glutamate, or D-tyrosine; E is an amino acid selected from the group consisting of L-phenylalanine, L-tryptophan and L-homotryptophan, or is L-1-naphthyl or L-3-benzothienyl alanine; F is the side chain of L-arginine, L-homoarginine, L-citrulline, or L-canavanine; and X 1 is —(CH 2 ) n NH— or (CH 2 ) n S—, where n is an integer from 1 to 4.
19 . The method of claim 18 , wherein A is NH-acyl; B is the side chain of L-phenylalanine; C is the side chain of L-proline; D is the side chain of D-cyclohexylalanine; E is the side chain of L-tryptophan; F is the side chain of L-arginine; and X 1 is —(CH 2 ) n NH—, where n is 3.
20 . A method of treatment of osteoarthritis, the method comprising the step of administering to a subject in need thereof, an effective amount of a pharmaceutically-acceptable composition that comprises a C5a G protein-coupled receptor inhibitor, wherein the inhibitor:
(a) is an antagonist of a C5a G protein-coupled receptor; (b) has substantially no agonist activity; and (c) is a cyclic peptide or peptidomimetic compound of formula I:
wherein A is NH-acyl; B is the side chain of L-phenylalanine; C is the side chain of L-proline; D is the side chain of D-cyclohexylalanine; E is the side chain of L-tryptophan;
F is the side chain of L-arginine; and X 1 is —(CH 2 ) n NH—, where n is 3.
21 . A method of treating osteoarthritis in a subject, the method comprising the step of administering to the subject an effective amount of a cyclic peptide or peptidomimetic compound selected from the group consisting of:
wherein the compound is a C5a G protein-coupled receptor antagonist that has substantially no agonist activity.
22 . The method of claim 21 , wherein the compound has the formula:
23 . The method of claim 21 , wherein the compound has the formula:
24 . The method of claim 21 , wherein the compound has the formula:
25 . The method of claim 21 , wherein the compound has the formula:
26 . A method for treating osteoarthritis in a mammal, the method comprising the step of: administering to a mammal in need thereof, an effective amount of a composition comprising a C5a G protein-coupled receptor antagonist compound that (a) has substantially no agonist activity and (b) is a cyclic peptide or peptidomimetic compound of formula I:
wherein A is NH-acyl; B is the side chain of L-phenylalanine; C is the side chain of L-proline; D is the side chain of D-cyclohexylalanine; E is the side chain of L-tryptophan; F is the side chain of L-arginine; and X 1 is —(CH 2 ) n NH—, where n is 3.Cited by (0)
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