Potent, selective pyrimidinetrione-based inhibitors of MMP-13

被引：42

作者：

Reiter, Lawrence A.

Freeman-Cook, Kevin D.

Jones, Christopher S.

Martinelli, Gary J.

Antipas, Amy S.

Berliner, Martin A.

Datta, Kaushik

Downs, James T.

Eskra, James D.

Forman, Michael D.

Greer, Elaine M.

Guzman, Roberto

Hardink, Joel R.

Janat, Fouad

Keene, Nandell F.

Laird, Ellen R.

Liras, Jennifer L.

Lopresti-Morrow, Lori L.

Mitchell, Peter G.

Pandit, Jayvardhan

Robertson, Donald

Sperger, Diana

Vaughn-Bowser, Marcie L.

Waller, Darra M.

Yocum, Sue A.

机构：

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

[2] Pfizer Global Res & Dev, Ann Arbor Labs, Ann Arbor, MI 48105 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 22期

关键词：

pyrimidinetrione; matrix metalloprotease; MMP-13; collagenase-3;

D O I：

10.1016/j.bmcl.2006.08.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and > 100-fold selectivity against other MMPs have been identified. Despite high molecular weights, c log Ps, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：5822 / 5826

页数：5

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