42 results about "Aggrecanase" patented technology

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.

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.

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.

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 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.

This invention is directed to aromatic sulfone hydroxamic acids (including hydroxamates) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and / or aggrecanase activity. This invention also is directed to a prevention or treatment method that comprises administering such a compound or salt in an MMP-inhibiting and / or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP and / or aggrecanase activity.

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).