P1'-联苯乙基羧基烷基二肽对基质溶解素-1（MMP-3）的抑制作用

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.

作者信息

Esser C K, Bugianesi R L, Caldwell C G, Chapman K T, Durette P L, Girotra N N, Kopka I E, Lanza T J, Levorse D A, MacCoss M, Owens K A, Ponpipom M M, Simeone J P, Harrison R K, Niedzwiecki L, Becker J W, Marcy A I, Axel M G, Christen A J, McDonnell J, Moore V L, Olszewski J M, Saphos C, Visco D M, Hagmann W K

机构信息

Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.

出版信息

J Med Chem. 1997 Mar 14;40(6):1026-40. doi: 10.1021/jm960465t.

DOI:10.1021/jm960465t

PMID:9083493

Abstract

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).

摘要

发现在P1'位置含有联苯乙基的羧烷基肽是基质溶解素-1（MMP-3）和明胶酶A（MMP-2）的有效抑制剂，抑制活性范围为10 - 50 nM，但对胶原酶（MMP-1）的抑制作用较弱。通过小鼠胸腔中放射性标记转铁蛋白的MMP-3降解体内模型测定，P1'处的联苯乙基部分、P2'处的叔丁基和P3'处的甲基组合产生了口服生物可利用的抑制剂。描述了一种P1-联苯抑制剂与MMP-3催化结构域复合物的X射线结构。事实证明，在P1'处含有卤代联苯乙基残基的抑制剂在酶活性和口服活性方面更具优势，其中2(R)-[2-(4'-氟-4-联苯基)乙基]-4(S)-正丁基-1,5-戊二酸1-(α(S)-叔丁基甘氨酸甲基酰胺)酰胺（L-758,354，26）对MMP-3的Ki为10 nM，在小鼠胸腔试验中的口服半数有效剂量（ED50）为11 mg/kg。该化合物在软骨破坏的急性（兔体内注射MMP-3和IL-1β）和慢性（大鼠佐剂性关节炎和小鼠胶原诱导性关节炎）模型中进行了评估，但仅在MMP-3注射模型中显示出活性（静脉注射半数有效剂量 = 6 mg/kg）。