Yuichiro Yabe

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.

A new synthetic route for the γ-lactone precursors of hydroxyethylene dipeptide isosteres

Abstract δ-Phthalimido-γ-ketoesters were obtained by the Pd catalysed coupling reaction between acid chlorides and organozinc reagents derived from β-iodoesters, and were converted into the γ-lactone precursors of Phe-ψ[H.E.]-Ala and Phe-ψ [H.E.]-Pro ( 15a,b–18a,b ).

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.

An efficient synthesis of γ-lactones as precursors of hydroxyethylene dipeptide isostere

An efficient and stereocontrolled synthesis of γ-lactones as precursors of the hydroxyethylene dipeptide isostere has been developed, starting from readily available 5-oxotetrahydrofuran-2-carboxylic acid 6.

Dipeptide renin inhibitors containing a bis[(1-naphthyl)methyl]acetyl group as the N-terminal component

The syntheses and biological activities of potent dipeptide renin inhibitors containing a bis[(1-napthyl)methyl]acetyl group as the N-terminal component are described.