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 a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 1998-05, Vol.6 (5), p.595-604
Main Authors: Takashiro, E, Watanabe, T, Nitta, T, Kasuya, A, Miyamoto, S, Ozawa, Y, Yagi, R, Nishigaki, T, Shibayama, T, Nakagawa, A, Iwamoto, A, Yabe, Y
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Biological Availability
Dogs
HIV Protease Inhibitors - chemistry
HIV Protease Inhibitors - pharmacokinetics
HIV Protease Inhibitors - pharmacology
HIV-1 - drug effects
Humans
Phenylbutyrates - chemistry
Spectrum Analysis
Structure-Activity Relationship
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Summary: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.
ISSN:0968-0896
DOI:10.1016/S0968-0896(98)00004-2