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.
Takashiro
E
E
Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
Watanabe
T
T
Nitta
T
T
Kasuya
A
A
Miyamoto
S
S
Ozawa
Y
Y
Yagi
R
R
Nishigaki
T
T
Shibayama
T
T
Nakagawa
A
A
Iwamoto
A
A
Yabe
Y
Y
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010654:Phenylbutyrates / Q000737:chemistry*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid