USE OF MEDIUM-SIZED CYCLOALKYL RINGS TO ENHANCE SECONDARY BINDING - DISCOVERY OF A NEW CLASS OF HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) PROTEASEINHIBITORS

A unique strategy for the enhancement of secondary binding of an inhib itor to an enzyme has been demonstrated in the design of new human imm unodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, K-1 = 0.800 mu M) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alk yl rings, the enzyme inhibitory activity of the resulting compounds wa s dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, K-i = 0.015 mu M) were obtained. X-ray crystal stru ctures of these inhibitors complexed with HIV protease indicated the c ycloalkyl rings were able to fold into the S1' pocket of the enzyme an d fill it much more effectively than the rigid benzene ring of the 4-h ydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HI V protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic st ructure, has already shown several advantages over peptidic inhibitors , including high oral bioavailability (91-99%), a relatively long half -life (4.9 h), and ease of synthesis (three steps).