STRUCTURE-ACTIVITY RELATIONSHIP OF HIV-1 PROTEASE INHIBITORS CONTAINING AHPBA - PART III - MODIFICATION OF P-2 SITE

The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhib itors containing AHPBA (3-amino-2-hydroxy-4-phenylbutanoic acid) is di scussed. In order to solve the problem of poor oral bioavailability, s mall-sized dipeptide HIV-1 protease inhibitors containing cyclic ureth anes or benzamides at the P-2 Site were designed and prepared. The sub stitution patterns of the benzamides contributed significantly to thei r HIV-1 PR inhibitory activities, and it was shown that the choice of P-2-residues was very important. Highly potent inhibitors possessing s ubnanomolar IC50 values and exhibiting good antiviral potency have bee n identified. In this class, inhibitor 18 was the most potent (IC90 (C EM/HIV-1 IIIB) 0.11 mu M) and showed good oral bioavailability in dogs . (C) 1998 Elsevier Science Ltd. All rights reserved.