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|1hfs, resolution 1.70Å ()|
CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004
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).
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[MMP3_HUMAN] Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:614466]. A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. Note=A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.
[MMP3_HUMAN] Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.
About this Structure
- 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.. Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides. J Med Chem. 1997 Mar 14;40(6):1026-40. PMID:9083493 doi:10.1021/jm960465t
- Nar H, Werle K, Bauer MM, Dollinger H, Jung B. Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor. J Mol Biol. 2001 Sep 28;312(4):743-51. PMID:11575929 doi:10.1006/jmbi.2001.4953
- ↑ Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996 May 31;271(22):13055-60. PMID:8662692
- ↑ Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002 Dec 12;347(24):1916-23. PMID:12477941 doi:10.1056/NEJMoa021445