Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors

被引：22

作者：

Ferraris, D ^{[1
]}

Ko, YS ^{[1
]}

Calvin, D ^{[1
]}

Chiou, T ^{[1
]}

Lautar, S ^{[1
]}

Thomas, B ^{[1
]}

Wozniak, K ^{[1
]}

Rojas, C ^{[1
]}

Kalish, V ^{[1
]}

Belyakov, S ^{[1
]}

机构：

[1] Guilford Pharmaceut Inc, 6611 Tributary St, Baltimore, MD 21224 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 22期

关键词：

DPP IV; diabetes; serine protease;

D O I：

10.1016/j.bmcl.2004.08.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S F binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG) and octahydroindole carboxylate (OIC) serve as the most potent S2 binding groups within each series. Stereochemistry at the a-position of the central ring is relevant to potency within the ketopyrrolidines series, but not in the keto-azetidine series. Finally, the ketoazetidines display enhanced stability over the corresponding ketopyrrolidines, while maintaining their potency. In fact, certain stabilized ketoazetidines can maintain their in vitro potency and inhibit DPP IV in the plasma for up to 6h. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：5579 / 5583

页数：5

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