65 results about "C5a receptor" patented technology

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.

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted dihydropyridines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of C5a receptors.

The invention relates to novel cyclic compounds which have the ability to modulate the activity of G protein-coupled receptors. The compounds preferably act as antagonists. In preferred embodiments, the invention provides cyclic peptidic and peptidomimetic antagonists of C5a receptors, which are active against C5a receptors on polymorphonuclear leukocytes and macrophages. The compounds of the invention are both potent and selective, and are useful in the treatment of a variety of inflammatory conditions.

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.

The present invention provides methods and compositions for treating and / or preventing age related macular degeneration and other conditions involving macular degeneration, ocular neovascularization, or ocular inflammation. The methods comprise administering a composition comprising a compound that is an antagonist of a G protein coupled receptor, e.g., the C5a receptor, to a subject in need of treatment or prevention of age-related macular degeneration or another condition involving macular degeneration or ocular neovascularization. The invention provides compositions comprising a compound that is an antagonist of a G protein coupled receptor linked either directly or indirectly to a moiety that binds to a component present on or at the surface of cell or noncellular molecular entity, e.g., a component present in the eye of a subject at risk of or suffering from age related macular degeneration or a related condition or choroidal neovascularization.

Methods for treating, preventing or delaying onset of tumor formation and other forms of cancer are disclosed. The methods involve administration of a complement inhibitor to inhibit C5a receptor signaling in the tumor microenvironment.

Described are methods for treating, preventing, or reducing the risk of, miscarriages, especially recurrent miscarriages. The methods comprise administering to a female subject a therapeutic agent that modulates the activity or binding of components of the complement system, together with a pharmaceutically acceptable carrier. For example, the therapeutic agent can be a C3-convertase inhibitor, an antibody against C5, an antagonist of the C5a receptor, or an antibody against factor B or factor D. Screening methods for agents that can prevent or reduce the risk of miscarriages, especially recurrent miscarriages, are also described.

The present invention relates to a urea derivative of the formula (1)wherein each symbol is as described in the specification, a pharmaceutically acceptable salt thereof and pharmaceutical use thereof. The compound of the present invention has a C5a receptor antagonistic action and is useful as an agent for the prophylaxis or treatment of diseases or syndromes due to inflammation caused by C5a [e.g., autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, cardiac infarction, brain infarction, psoriasis, Alzheimer's disease and serious organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the like) due to activation of leukocytes caused by ischemia, trauma, burn, surgical invasion and the like]. In addition, it is useful as an agent for the prophylaxis or treatment of infectious diseases caused by bacteria or virus that invades via a C5a receptor.

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of C5a receptors.

The invention relates to novel cyclic compounds which have the ability to modulate the activity of G protein-coupled receptors. The compounds preferably act as antagonists. In preferred embodiments, the invention provides cyclic peptidic and peptidomimetic antagonists of C5a receptors, which are active against C5a receptors on polymorphonuclear leukocytes and macrophages. The compounds of the invention are both potent and selective, and are useful in the treatment of a variety of inflammatory conditions.

The present invention provides novel compounds of Formula I which are antagonists of the C5a receptor. Compounds of the present invention are useful for the treatment of various C5a-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of C5a-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of C5a receptors.

Methods for treating, preventing or delaying onset of polyp formation and subsequent colon cancer are disclosed. The methods involve administration of a complement inhibitor to inhibit C5a receptor signaling in the tumorigenic or pre-tumorigenic tissue.

The invention relates to the prevention or treatment of a systemic injury which is secondary to a burn, such as dysfunction or failure of an organ secondary to a burn, with an antagonist of a C5a receptor. In one embodiment the invention relates to the prevention or treatment of dysfunction or failure of the lung, kidney, bowel and / or liver which is secondary to a burn.

This invention relates to the treatment of neurological conditions with novel cyclic peptidic and peptidomimetic compounds which have the ability to modulate the activity of C5a receptors. The compounds preferably act as antagonists of the C5a receptor, and are active against C5a receptors on polymorphonuclear leukocytes, monocytes, lymphocytes and / or macrophages. In a preferred form of the invention the neurological conditions are neurodegenerative diseases, neuroimmunological disorders, diseases arising from dysfunction of the blood brain barrier, and stroke.

This invention relates to the use of an antagonist of a G protein-coupled receptor in the prevention and / or treatment of fibrosis, such as the treatment of fibrosis associated with myocardial infarction or diabetes or certain pulmonary conditions. In a preferred embodiment, the antagonist is a C5a receptor antagonist, more preferably a cyclic peptide antagonist of the C5a receptor. In particular, the invention provides a method of prevention, treatment or alleviation of a fibrotic condition, comprising the step of administering an effective amount of an antagonist of a G protein-coupled receptor to a subject in need of such treatment.

PL37 (RAARISLGPRCIKAFTE [SEQ ID NO: 2]) is an Antisense Homology Box peptide composed of amino acids 37 to 53 of C5a-anaphylatoxin. Complementary peptides, ASGAPAPGPAGPLRPMF (Pep-A [SEQ ID NO: 1]) and ASTAPARAGLPRLPKFF (Pep-B [SEQ ID NO: 3]) were designed and characterized. Pep-A bound to PL37 and to C5a with very slow dissociation, whereas Pep-B failed to bind at all. C5a was inactivated by 7 nM or more of Pep-A and this concentration of Pep-A inhibited induction of intracellular Ca++ influx in neutrophils. Patch clamp studies also showed the effectiveness of Pep-A in C5a-receptor-expressing neuroblastoma cells. Pep-A administration prevented rats from C5a-mediated rapid lethal shock. A-Pep-A (Pep-A acetylated with alanine at the amino-terminus) was more stable in vivo and showed stronger inhibition of inflammatory reactions in mice and rats. Chemical modification of Pep-A (e.g., acetylation, or single or multiple amino acid replacement, insertion, or deletion within the native Pep-A sequence) will yield effective inhibitors, and will often improve inhibitory function on C5a anaphylatoxin. In such modified constructs it will often be desired to conserve some or all 5 prolines found in Pep-A to preserve inhibitory function on C5a.

This invention relates to the treatment of neurological conditions with novel cyclic peptidic and peptidomimetic compounds which have the ability to modulate the activity of C5a receptors. The compounds preferably act as antagonists of the C5a receptor, and are active against C5a receptors on polymorphonuclear leukocytes, monocytes, lymphocytes and / or macrophages. In a preferred form of the invention the neurological conditions are neurodegenerative diseases, neuroimmunological disorders, diseases arising from dysfunction of the blood brain barrier, and stroke.

The invention relates to a C5a receptor antagonist of structure (I), wherein X1 is a radical having a mass of about 1-300 and stands for R5-, R5-CO—, R5-N(R6)-CO—, R5-O—CO—, R5-SO2—, R5-N(R6)-SO2—, R5-N(R6)-, R5-N(R6)-CS—, R5-N(R6)-C(NH)—, R5-CS—, R5-P(O)OH—, R5-B(OH)— or R5-CH═N—O—CH2—CO—, wherein R5 / R6 represent H, F, hydroxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, alkoxy, alkoxyalkyl, substituted alkoxyalkyl, aryloxyalkyl or substituted aryloxyalkyl; X2=radical (biological bonding properties of a mimicrying phenylalanine unit); X3 / X4=spacer (amino acids, amino-acid analogs and amino-acid derivatives); X5=radical (biological bonding properties of a mimicrying cyclohexylalanine or homoleucine unit); X6=radical (biological bonding properties of a mimicrying tryptophan unit); X7=radical (biological bonding properties of a mimicrying norleucine or phenylalanine unit), a chemical bond being formed between X3 and X7.

The present disclosure provides, inter alia, Compounds of Formula (I)or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.

A preservation solution for organs waiting to be transplanted is disclosed; the method of using the solution in a transplantation procedure is also disclosed. The preservation solutions comprise a balanced isotonic aqueous solution comprising sodium, potassium, calcium, magnesium and bicarbonate ions in a physiologically acceptable amount, together with an effective amount of a mutein of the C5a anaphylatoxin which is a C5a receptor antagonist wherein the amino acid residue naturally occurring at sequence position 69 is mutated.

The present invention relates to fused piperidinyl bicyclic, meta-substituted piperidinyl and their related compounds that modulate activities of mammalian C5a receptor by directly binding to the C5a receptor. The invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of a disease or a disorder involving pathogenic activation of C5a receptors.

The present invention provides novel compounds of Formula I which are antagonists of the C5a receptor. Compounds of the present invention are useful for the treatment of various C5a-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of C5a-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.

This invention relates to the use of an antagonist of a G protein-coupled receptor in the prevention and / or treatment of fibrosis, such as the treatment of fibrosis associated with myocardial infarction or diabetes or certain pulmonary conditions. In a preferred embodiment, the antagonist is a C5a receptor antagonist, more preferably a cyclic peptide antagonist of the C5a receptor. In particular, the invention provides a method of prevention, treatment or alleviation of a fibrotic condition, comprising the step of administering an effective amount of an antagonist of a G protein-coupled receptor to a subject in need of such treatment.

The present invention relates to a urea derivative of the formula (1) wherein each symbol is as described in the specification, a pharmaceutically acceptable salt thereof and pharmaceutical use thereof. The compound of the present invention has a C5a receptor antagonistic action and is useful as an agent for the prophylaxis or treatment of diseases or syndromes due to inflammation caused by C5a [e.g., autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, cardiac infarction, brain infarction, psoriasis, Alzheimer's disease and serious organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the like) due to activation of leukocytes caused by ischemia, trauma, burn, surgical invasion and the like]. In addition, it is useful as an agent for the prophylaxis or treatment of infectious diseases caused by bacteria or virus that invades via a C5a receptor.

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.