42 results about "Aggrecanase" patented technology

The present invention relates to modulators of metalloproteinase activity.

This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC50s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: or a therapeutically acceptable salt thereof, whereinX is carbon or nitrogen;R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R1 and R2 is methyl;R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R3 and R4 may be taken together to form a carbonyl group; andR5 and R6 are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl;with the provisos:when X is carbon, then R7 and R8 are both hydrogen and at least one of R1, R2, R3, and R4 is hydroxy;when X is carbon and R5 is para-halo, then at least one of R6, R3, and R4 is not hydrogen;when X is nitrogen, then R8 is not present and R7 is hydrogen or a group of the formula: wherein, Y is —CH2—NH2 or —NH—CH3; andwhen X is nitrogen and R7 is H, then R3 and R4 are taken together to form a carbonyl group.

This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC50s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R1 and R2 is methyl; R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R3 and R4 may be taken together to form a carbonyl group; and R5 and R6 are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl; with the provisos: when X is carbon, then R7 and R8 are both hydrogen and at least one of R1, R2, R3, and R4 is hydroxy; when X is carbon and R5 is para-halo, then at least one of R6, R3, and R4 is not hydrogen; when X is nitrogen, then R8 is not present and R7 is hydrogen or a group of the formula: wherein, Y is —CH2—NH2 or —NH—CH3; and when X is nitrogen and R7 is H, then R3 and R4 are taken together to form a carbonyl group.

Human aggrecanase and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptides and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications. Also provided are methods of inhibiting aggrecanase activity in a host and methods of treating disease conditions associated with aggrecanase activity, e.g. rheumatoid arthritis, osteo-arthritis, infectious arthritis, gouty arthritis, psoriatic arthritis, spondolysis, sports injury, joint trauma, pulmonary disease, fibrosis, and the like.

A sultam derivative of Formula (1) described below having inhibitory action for aggrecanase activity is provided. The sultam derivative of Formula (1) and a salt thereof exhibit strong inhibitory action for aggrecanase activity in a living body of a mammalian animal including human, and is useful, for example, as an active ingredient of a pharmaceutical agent for preventing and / or treating various diseases caused by degradation of aggrecan.

The present invention relates to methods of treating ADAMTS-5-associated diseases and particularly osteoarthritis comprising administering an agent capable of modulating ADMATS-5 activity to a subject afflicted with the disease. The agent is preferably a biaryl sulfonamide compound. The invention is based, in part, on the discovery that transgenic animals that do not express functional ADAMTS-5 show a reduction in the degree of osteoarthritis after the induction of osteoarthritis as compared to WT animals. Furthermore, the ADAMTS-5 transgenic animals have reduced aggrecanase activity in articular tissue as compared to WT animals. These animals are good models for ADAMTS-5-associated diseases, and for screening of drugs useful in the treatment and / or prevention of these diseases. There are no other animal models in which the deletion of the activity of a single gene is capable of abrogating the course of osteoarthritis. Accordingly, these animals also show that osteoarthritis can be prevented and / or treated by administering to a subject an ADAMTS-5 inhibitory agent and particularly an agent capable of inhibiting the aggrecanase activity of ADAMTS-5.

Novel aggrecanase proteins and the nucleotide sequences encoding them as well as processes for producing them are disclosed. Methods of identifying and developing inhibitors of the aggrecanase enzymes and antibodies to the enzymes for treatment of conditions characterized by the degradation of aggrecan are also disclosed.

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1):wherein R1 is —(CH2)m—X—(CH2)n-A1 etc., wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc. and A1 is a substituted C3-14 hydrocarbon ring group, etc.; R2 and R3 are the same or different and each is a hydrogen atom, —(CH2)p—X1—(CH2)q-A2, etc., wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc. and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc.; R4 is —CO2R9, etc., wherein R9 is a hydrogen atom, etc.; and R20 and R21 are the same or different and each is a hydrogen atom, —(CH2)m12—X12—(CH2)m12—R30, etc., wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc. and R30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a N-substituted-N-sulfonylaminocyclopropane compound of formula (1): wherein R1 is —W-A1—W1-A2, W is —(CH2)m—X—(CH2)n—, wherein W1 is —(CH2)m1—X1—(CH2)n1—, m, m1, n and n1 are the same or different and each is 0 to 6, X and X1 are the same or different and each is a single bond, etc., A1 is an optionally substituted C3-14 hydrocarbon ring group, etc. and A2 is a substituted C3-14 hydrocarbon ring group etc.; R2 is —(CH2)r—CO—R8, etc., wherein r is 0 to 6 and R8 is a C1-6 alkoxy group, etc.; R3 and R4 are the same or different and each is a hydrogen atom, a C1-6 alkyl group, etc.; and R5 is —CO2R21 etc.; R30 and R31 are the same or different and each is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

A novel polypeptide, a polynucleotide encoding this polypeptide, an expression vector comprising this polynucleotide, a cell transfected with the expression vector, an antibody binding to the above polypeptide, a convenient screening method for obtaining an agent for treating joint diseases, and a process for manufacturing a pharmaceutical composition for treating joint diseases are disclosed. The polypeptide is a novel aggrecanase causative of joint diseases (particularly an OA disease).

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R1 is —(CH2)m—X—(CH2)n-A1 etc., wherein m and n are the same or different and each is 0 to 6, X1 is a single bond, etc. and A1 is a substituted C3-14 hydrocarbon ring group, etc.; R2 and R3 are the same or different and each is a hydrogen atom, —(CH2)p—X1-(CH2)q-A2, etc., wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc. and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc.; R4 is —CO2R9, etc., wherein R9 is a hydrogen atom, etc.; and R20 and R21 are the same or different and each is a hydrogen atom, —(CH2)m12—X12—(CH2)m12—R30, etc., wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc. and R30 is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a N-substituted-N-sulfonylaminocyclopropane compound of formula (1)wherein R1 is —W-A1-W1-A2, W is —(CH2)m—X—(CH2)n—, wherein W1 is —(CH2)m1—X1—(CH2)n1—, m, m1, n and n1 are the same or different and each is 0 to 6, X and X1 are the same or different and each is a single bond, etc., A1 is an optionally substituted C3-14 hydrocarbon ring group, etc. and A2 is a substituted C3-14 hydrocarbon ring group etc.; R2 is —(CH2)r—CO—R8, etc., wherein r is 0 to 6 and R8 is a C1-6 alkoxy group, etc.; R3 and R4 are the same or different and each is a hydrogen atom, a C1-6 alkyl group, etc.; and R5 is —CO2R21, etc.; R30 and R31 are the same or different and each is a hydrogen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

This present invention discloses inhibitors of matrix metalloproteinases, and novel methods of their use. The inhibitors may be useful for treating conditions that involve enhanced activity of at least one of the matrix metalloproteinases neutrophil collagenase (MMP-8), aggrecanase, hADAMTS1, and gelatinase A (MMP-2). Such disorders may include, but are not limited to, degenerative joint disorders (e.g., osteoarthroses), spondyloses, chondrolysis associated with joint trauma or prolonged joint immobilization (often occurring after meniscus or patellar injuries or ligament tears), connective tissue disorders (e.g., collagenoses), wound healing disturbances, periodontal disorders, chronic disorders of the locomotor system (e.g., inflammatory, immunologically, or metabolism-related acute and chronic arthritides), arthropathies, myalgias, or disturbances of bone metabolism.

This invention relates to compounds of the Formulae (I)-(IX): or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, aggrecanase, ADMP, LpxC, ADAMs, TACE, TNF-α or combinations thereof.

This invention is directed to assays to determine the presence or absence of proteins that exhibit aggrecanase or ADMP activity. This invention also relates to peptides that acts as a substrates for ADMPs, their use in various assays to determine the presence or absence of ADMP activity, and their use as inhibitors of ADMP activity.

The invention is directed to the family of aggrecan degrading metallo proteases (ADMPs) that exhibit the ability to cleave the aggrecan core protein between amino acid residues Glu373-Ala374. The invention encompasses the nucleic acids encoding such enzymes, processes for production of recombinant ADMPs, compositions containing such enzymes, and the use of these enzymes in various assays and for the development of novel inhibitors for use as therapies for diseases involving aggrecanase-mediated degradation of cartilage or other aggrecanase-associated diseases.

This invention relates to compounds of the Formulae (I)-(IX), or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, aggrecanase, ADMP, LpxC, ADAMs, TACE, TNF-a or combinations thereof.

The present invention describes synthetic peptide substrates of the metalloproteases, agggrecanase-1 and / or -2 suitable for assays of enzyme activity. The invention also describes methods using these peptides to discover pharmaceutical agents that modulate these proteases.

Truncated aggrecanase proteins and nucleotides sequences encoding them as well as processes for producing them are disclosed. Additionally, aggrecanases with amino acid mutations that lead to increased stability and expression levels in comparison with wild-type or native aggrecanases are also disclosed. Aggrecanases of the invention are especially useful for development of compositions for treatment of diseases such as osteoarthritis. Methods for developing inhibitors of the aggrecanase enzymes and antibodies to the enzymes for treatment of conditions characterized by the degradation of aggrecan are also disclosed.

The present invention provides an antibody that specifically binds to human aggrecanase, and inhibits enzymatic activity of the human aggrecanase. In one embodiment, aggrecanase is ADAMTS4. In one embodiment, the antibody recognizes a particular epitope in human ADAMTS4, and inhibits not only aggrecanase activity of human ADAMTS4 but also aggrecanase activity of human ADAMTS5. In addition, the present invention also provides use of said antibody in the prophylaxis or treatment of the progression of arthritis.

The present invention relates to modulators of metalloproteinase activity.

Novel aggrecanase proteins and the nucleotide sequences encoding them as well as processes for producing them are disclosed. Methods of identifying and developing inhibitors of the aggrecanase enzymes and antibodies to the enzymes for treatment of conditions characterized by the degradation of aggrecan are also disclosed.

The invention relates to the field of obesity and related metabolic diseases. More specifically, the invention relates to methods of reducing aggrecanase activity or antigen in mammals in order to enhance brown adipose tissue (BAT) development, to promote conversion of white adipose tissue (WAT) into BAT in vivo, and to limit triglyceride accumulation and steatosis in the liver. The invention also relates to a strategy of neutralization or depletion of ADAMTS5 as a strategy to inhibit adipogenesis and more specifically, the invention relates to a method of reducing aggracanase-2 (ADAMTS5, A Disintegrin and Metalloproteinase with Thrombospondin motif 1; member 5) antigen and / or activity in mammals in order to impair differentiation of precursor cells into mature adipocytes (i.e., adipogenesis).

This invention is directed generally to hydroxamic acid and amide compounds (including salts of such compounds), and, more particularly, to aryl- and heteroaryl-arylsulfonylmethyl hydroxamic acids and amides that, inter alia, inhibit protease activity, particularly matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and / or aggrecanase activity. These compounds generally correspond in structure to Formula I: wherein A1, A2, A3, E1, E2, E3, and E4 are as defined in this patent. This invention also is directed to compositions of such compounds, intermediates for the syntheses of such compounds, methods for making such compounds, and methods for treating conditions associated with MMP activity and / or aggrecanase activity, particularly pathological conditions.

Provided herein is a method for identifying a patient as a candidate for treatment with an aggrecanase inhibitor. Also provided is a method of evaluating the effectiveness of an aggrecanase inhibitor.

A novel use of ADAMTS-1 protein or its functionally equivalent modifications; medicinal compositions for treating or preventing diseases caused by abnormal chondral remodeling, medicinal compositions for normalizing abnormal chondral remodeling, and medicinal compositions for decomposing aggrecan, each containing, as the active ingredient, ADAMTS-1 protein or its functionally equivalent modifications; and a method whereby an aggrecanase activity regulator useful in treating or preventing diseases caused by the depression or acceleration of aggrecanase activity can be screened. ADAMTS-1 protein or its functionally equivalent modifications are usable in producing drugs for treating or preventing diseases caused by abnormal chondral remodeling, drugs for normalizing abnormal chondral remodeling or drugs for decomposing aggrecan.

Novel aggrecanase proteins and the nucleotide sequences encoding them as well as processes for producing them are disclosed. Methods for developing inhibitors of the aggrecanase enzymes and antibodies to the enzymes for treatment of conditions characterized by the degradation of aggrecan are also disclosed.