Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14

被引：53

作者：

Blagg, JA ^{[1
]}

Noe, MC ^{[1
]}

Wolf-Gouveia, LA ^{[1
]}

Reiter, LA ^{[1
]}

Laird, ER ^{[1
]}

Chang, SPP ^{[1
]}

Danley, D ^{[1
]}

Downs, JT ^{[1
]}

Elliott, NC ^{[1
]}

Eskra, JD ^{[1
]}

Griffiths, RJ ^{[1
]}

Hardink, JR ^{[1
]}

Haugeto, AI ^{[1
]}

Jones, CS ^{[1
]}

Liras, JL ^{[1
]}

Lopresti-Morrow, LL ^{[1
]}

Mitchell, PG ^{[1
]}

Pandit, J ^{[1
]}

Robinson, RP ^{[1
]}

Subramanyam, C ^{[1
]}

Vaughn-Bowser, ML ^{[1
]}

Yocum, SA ^{[1
]}

机构：

[1] Pfizer Inc, Global Res & Dev, Groton Labs, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 07期

关键词：

MMP-13; matrix metalloproteinase; osteoarthritis;

D O I：

10.1016/j.bmcl.2005.02.038

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S-I' pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 NIMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：1807 / 1810

页数：4

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