Indole inhibitors of human nonpancreatic secretory phospholipase A(2) .1. Indole-3-acetamides

被引：91

作者：

Dillard, RD ^{[1
]}

Bach, NJ ^{[1
]}

Draheim, SE ^{[1
]}

Berry, DR ^{[1
]}

Carlson, DG ^{[1
]}

Chirgadze, NY ^{[1
]}

Clawson, DK ^{[1
]}

Hartley, LW ^{[1
]}

Johnson, LM ^{[1
]}

Jones, ND ^{[1
]}

McKinney, ER ^{[1
]}

Mihelich, ED ^{[1
]}

Olkowski, JL ^{[1
]}

Schevitz, RW ^{[1
]}

Smith, AC ^{[1
]}

Snyder, DW ^{[1
]}

Sommers, CD ^{[1
]}

Wery, JP ^{[1
]}

机构：

[1] ELI LILLY & CO, LILLY RES LABS, LILLY CORP CTR, INDIANAPOLIS, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1996年 / 39卷 / 26期

关键词：

D O I：

10.1021/jm960485v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A(2) (hnps-PLA(2)) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA(2). One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure-activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA(2) which were of great value in directing the SAR.

引用

页码：5119 / 5136

页数：18

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