INDOLE INHIBITORS OF HUMAN NONPANCREATIC SECRETORY PHOSPHOLIPASE A(2).2. INDOLE-3-ACETAMIDES WITH ADDITIONAL FUNCTIONALITY

As reported in our previous paper, a series of indole-3-acetamides whi ch possessed potency and selectivity as inhibitors of human nonpancrea tic secretory phospholipase A(2)(hnps-PLA(2)) was developed. The desig n of these compounds was based on information derived from x-ray cryst al structures determined for complexes between the enzyme and its inhi bitors. We describe here the further implementation of this structure- based design strategy and continued SAR development to produce indole- 3-acetamides with additional functionalities which provide increased i nteraction with important residues within the enzyme active site. Thes e efforts led to inhibitors with substantially enhanced potency and se lectivity.