ABSTRACT
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Subject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfones/chemical synthesis , Amides/chemistry , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Rats , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cardiovascular Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cattle , Crystallography, X-Ray , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Hypertrophy, Left Ventricular/drug therapy , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Osteoarthritis is characterized by the loss of aggrecan and collagen from the cartilage extracellular matrix. The proteinases responsible for the breakdown of cartilage aggrecan include ADAMTS-4 (aggrecanase 1) and ADAMTS-5 (aggrecanase 2). Post-translational inhibition of ADAMTS-4/-5 activity may be important for maintaining normal homeostasis of aggrecan metabolism, and thus, any disruption to this inhibition could lead to accelerated aggrecan breakdown. To date TIMP-3 (tissue inhibitor of matrix metalloproteinases-3) is the only endogenous inhibitor of ADAMTS-4/-5 that has been identified. In the present studies we identify alpha(2)-macroglobulin (alpha(2)M) as an additional endogenous inhibitor of ADAMTS-4 and ADAMTS-5. alpha(2)M inhibited the activity of both ADAMTS-4 and ADAMTS-5 in a concentration-dependent manner, demonstrating 1:1 stoichiometry with second-order rate constants on the order of 10(6) and 10(5) m(-1) s(-1), respectively. Inhibition of the aggrecanases was mediated by proteolysis of the bait region within alpha(2)M, resulting in physical entrapment of these proteinases. Both ADAMTS-4 and ADAMTS-5 cleaved alpha(2)M at Met(690)/Gly(691), representing a novel proteinase cleavage site within alpha(2)M and a novel site of cleavage for ADAMTS-4 and ADAMTS-5. Finally, the use of the anti-neoepitope antibodies to detect aggrecanase-generated alpha(2)M-fragments in synovial fluid was investigated and found to be uninformative.
