US2009004264A1PendingUtilityA1
Methods for treating and ameliorating the symptons of inflammatory bowel diseases
Est. expiryOct 16, 2022(expired)· nominal 20-yr term from priority
A61P 29/00A61P 31/00A61P 31/04A61P 1/04A61K 38/12C07K 16/241A61K 2039/505A61P 1/00
54
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Claims
Abstract
This invention relates to methods of treatment of inflammatory bowel disease, 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 methods of the invention are disclosed.
Claims
exact text as granted — not AI-modified1 . A method of treatment of inflammatory bowel disease, comprising the step of administering an effective amount of an inhibitor of a C5a receptor to a subject in need of such treatment, in which the inhibitor is a compound that
is an antagonist of a C5a receptor,
and
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 the side chain of a D - or L -amino acid, but is not the side chain of glycine, D -phenylalanine, L -homophenylalanine, L -tryptophan, L -homotryptophan, L -tyrosine, or L -homotyrosine;
C is the side chain of a D -, L - or homo-amino acid, but is not the side chain of isoleucine, phenylalanine, or cyclohexylalanine;
D is the side chain of a neutral D -amino acid, but is not the side chain of glycine or D -alanine, a bulky planar side chain, or a bulky charged side chain;
E is a bulky substituent, but is not the side chain of D -tryptophan, L -N-methyltryptophan, L -homophenylalanine, L -2-naphthyl L -tetrahydroisoquinoline, L -cyclohexylalanine, D -leucine, L -fluorenylalanine, or L -histidine;
F is the side chain of L -arginine, L -homoarginine, L -citrulline, or L -canavanine; and
X 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 - 23 . (canceled)
24 . The method of claim 1 , in which n is 2 or 3.
25 . The method of claim 1 , in which A is an acetamide group, an aminomethyl group, or a substituted or unsubstituted sulphonamide group.
26 . The method of claim 1 , in which A is a substituted sulphonamide, and the substituent is an alkyl chain of 1 to 6 carbon atoms, or a phenyl or toluoyl group.
27 . The method of claim 26 , in which the substituent is an alkyl chain of 1 to 4 carbon atoms.
28 . The method of claim 1 , in which B is the side chain of L -phenylalanine or L -phenylglycine.
29 . The method of claim 1 , in which C is the side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline.
30 . The method of claim 1 , in which D is the side chain of D -Leucine, D -homoleucine, D -cyclohexylalanine, D -homocyclohexylalanine, D -valine, D -norleucine, D -homonorleucine, D -phenylalanine, D -tetrahydroisoquinoline, D -glutamine, D -glutamate, or D -tyrosine.
31 . The method of claim 1 , in which 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-napthyl or L -3-benzothienyl alanine.
32 . The method of claim 1 , wherein said inhibitor has potent antagonist activity at sub-micromolar concentrations.
33 . The method of claim 1 , wherein said compound has a receptor affinity IC 50 <25 μM, and an antagonist potency IC 50 <1 μM.
34 . The method of claim 1 , wherein said compound is selected from the group consisting of:
AcF-[OPdChaWR] (PMX53),
35 . The method of claim 1 , wherein said compound is AcF-[OPdChaWR] (PMX53).
36 . The method of claim 1 , wherein said inhibitor is used in conjunction with one or more other agents for the treatment of inflammatory bowel disease.
37 . The method of claim 36 , wherein said other agent is infliximab or is an inhibitor of C3a.
38 . The method of claim 1 , wherein said inflammatory bowel disease is ulcerative colitis.
39 . The method of claim 1 , wherein said inflammatory bowel disease is Crohn's disease.
40 . The method of claim 1 , wherein said inhibitor is administered in an enteric coated capsule or per-rectally.
41 . A method of treating or ameliorating the symptoms of an inflammatory bowel disease in a mammal, said method comprising the step of administering to a mammal in need thereof, an amount of a compound of the formula (AcF-[OPdChaWR]) effective to treat or ameliorate the symptoms of said disease in said mammal.
42 . A method of ameliorating one or more symptoms of an inflammatory bowel disease in a mammal, said method comprising the step of administering to a mammal in need thereof, an amount of a C5a receptor antagonist compound effective to ameliorate said one or more symptoms of said inflammatory bowel disease in said mammal, wherein said compound comprises 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 the side chain of a D - or L -amino acid, but is not the side chain of glycine, D -phenylalanine, L -homophenylalanine, L -tryptophan, L -homotryptophan, L -tyrosine, or L -homotyrosine;
C is the side chain of a D -, L - or homo-amino acid, but is not the side chain of isoleucine, phenylalanine, or cyclohexylalanine;
D is the side chain of a neutral D -amino acid, but is not the side chain of glycine or D -alanine, a bulky planar side chain, or a bulky charged side chain;
E is a bulky substituent, but is not the side chain of D -tryptophan, L -N-methyltryptophan, L -homophenylalanine, L -2-naphthyl L -tetrahydroisoquinoline, L -cyclohexylalanine, D -leucine, L -fluorenylalanine, or L -histidine;
F is the side chain of L -arginine, L -homoarginine, L-citrulline, or L -canavanine; and
X 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.
43 . A method of treating an inflammatory bowel disease in a mammal, said method comprising the step of administering to a mammal in need thereof, an amount of a C5a receptor antagonist compound effective to treat said inflammatory bowel disease in said mammal, wherein said compound comprises 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 the side chain of a D - or L -amino acid, but is not the side chain of glycine, D -phenylalanine, L -homophenylalanine, L -tryptophan, L -homotryptophan, L -tyrosine, or L -homotyrosine;
C is the side chain of a D -, L - or homo-amino acid, but is not the side chain of isoleucine, phenylalanine, or cyclohexylalanine;
D is the side chain of a neutral D -amino acid, but is not the side chain of glycine or D -alanine, a bulky planar side chain, or a bulky charged side chain;
E is a bulky substituent, but is not the side chain of D -tryptophan, L -N-methyltryptophan, L -homophenylalanine, L -2-naphthyl L -tetrahydroisoquinoline, L -cyclohexylalanine, D -leucine, L -fluorenylalanine, or L -histidine;
F is the side chain of L -arginine, L -homoarginine, L -citrulline, or L -canavanine; and
X 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.
44 . The method of claim 42 or claim 43 , wherein said compound is selected from the group consisting of:
AcF-[OPdChaWR],
45 . A method of treating or ameliorating the symptoms of ulcerative colitis or Crohn's disease in a mammal, said method comprising the step of administering to a mammal in need thereof, an amount of a compound selected from the group consisting of:
(AcF-[OPdChaWR]),
effective to treat or ameliorate the symptoms of said ulcerative colitis or Crohn's disease in said mammal.Join the waitlist — get patent alerts
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