1hfs: Difference between revisions

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CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004

OverviewOverview

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).

About this StructureAbout this Structure

1HFS is a Single protein structure of sequence from Homo sapiens with ZN, CA and L04 as ligands. Active as Stromelysin 1, with EC number 3.4.24.17 Structure known Active Sites: CA1, CA2, CA3, L04, ZN1 and ZN2. Full crystallographic information is available from OCA.

ReferenceReference

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides., Esser CK, Bugianesi RL, Caldwell CG, Chapman KT, Durette PL, Girotra NN, Kopka IE, Lanza TJ, Levorse DA, MacCoss M, Owens KA, Ponpipom MM, Simeone JP, Harrison RK, Niedzwiecki L, Becker JW, Marcy AI, Axel MG, Christen AJ, McDonnell J, Moore VL, Olszewski JM, Saphos C, Visco DM, Hagmann WK, et al., J Med Chem. 1997 Mar 14;40(6):1026-40. PMID:9083493

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