1hfs: Difference between revisions

Carboxyalkyl peptides containing a biphenylylethyl group at the P1', position were found to be potent inhibitors of stromelysin-1 (MMP-3) and, gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of, collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a, tert-butyl group at P2', and a methyl group at P3' produced orally, bioavailable inhibitors as measured by an in vivo model of MMP-3, degradation of radiolabeled transferrin in the mouse pleural cavity. The, X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic, domain of MMP-3 is described. Inhibitors that contained halogenated, biphenylylethyl residues at P1' proved to be superior in terms of enzyme, potency and oral activity with, 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid, 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a, Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural, cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta, injection in the rabbit) and chronic (rat adjuvant-induced arthritis and, mouse collagen-induced arthritis) models of cartilage destruction but, showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

1HFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, CA and L04 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Structure known Active Sites: CA1, CA2, CA3, L04, ZN1 and ZN2. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HFS OCA].  

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