Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

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Dillard RD, Bach NJ, Draheim SE, Berry DR, Carlson DG, Chirgadze NY, Clawson DK, Hartley LW, Johnson LM, Jones ND, McKinney ER, Mihelich ED, Olkowski JL, Schevitz RW, Smith AC, Snyder DW, Sommers CD, Wery JP

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

J Med Chem. 1996 Dec 20;39(26):5119-36.

PubMed ID

9005255 [ View in PubMed

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Abstract

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 A2 (hnps-PLA2) 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-PLA2. 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-PLA2 which were of great value in directing the SAR.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(1-Benzyl-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid	Phospholipase A2, membrane associated	IC 50 (nM)	13600	N/A	N/A	Details