INDOLE INHIBITORS OF HUMAN NONPANCREATIC SECRETORY PHOSPHOLIPASE A(2).1. INDOLE-3-ACETAMIDES

Phospholipases (PLAs) produce rate-limiting precursors in the biosynth esis of various types of biologically active lipids involved in inflam matory processes. Increased levels of human nonpancreatic secretory ph ospholipase A(2) (hnps-PLA(2)) have been detected in several pathologi cal conditions. An inhibitor of this enzyme could have therapeutic uti lity. A broad screening program was carried out to identify chemical s tructures which could inhibit hnps-PLA(2). One of the lead compounds g enerated by the screening program was thoxy-2-methyl-1-(phenylmethyl)- 1H-indole-3-acetic acid (13a). We describe the syntheses, structure-ac tivity relationships, and pharmacological activities of a series of in dole-3-acetamides and related compounds derived from this lead. This S AR was undertaken with the aid of X-ray crystal structures of complexe s between the inhibitors and hnps-PLA(2) which were of great value in directing the SAR.