Author/Authors :
Eiji Takashiro، نويسنده , , Takashi Watanabe، نويسنده , , Tamayo Nitta، نويسنده , , Atsushi Kasuya، نويسنده , , Shuichi Miyamoto، نويسنده , , Yuji Ozawa، نويسنده , , Ryuichi Yagi، نويسنده , , Takashi Nishigaki، نويسنده , , Takahiro Shibayama، نويسنده , , Akihiko Nakagawa، نويسنده , , Aikichi Iwamoto، نويسنده , , Yuichiro Yabe، نويسنده ,
Abstract :
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 μM) and showed good oral bioavailability in dogs.
