Ryuichi Yagi

Structure–activity relationship of HIV-1 protease inhibitors containing α-hydroxy-β-amino acids. Detailed study of P1 site

Abstract The structure–activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing α-hydroxy-β-amino acids is discussed. We demonstrated that substituent groups on the P 1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P 1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P 2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC 90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.

Structure–activity relationship of HIV-1 protease inhibitors containing AHPBA. Part III: modification of P2 site

The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing AHPBA (3-amino-2-hydroxy-4-phenylbutanoic acid) is discussed. In order to solve the problem of poor oral bioavailability, small-sized dipeptide HIV-1 protease inhibitors containing cyclic urethanes or benzamides at the P2 site were designed and prepared. The substitution patterns of the benzamides contributed significantly to their HIV-1 PR inhibitory activities, and it was shown that the choice of P2-residues was very important. Highly potent inhibitors possessing subnanomolar IC50 values and exhibiting good antiviral potency have been identified. In this class, inhibitor 18 was the most potent (IC90 (CEM/HIV-1 IIIB) 0.11 microM) and showed good oral bioavailability in dogs.