Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

作者：Ghosh Arun K^*; Rao Kalapala Venkateswara; Nyalapatla Prasanth R; Osswald Heather L; Martyr Cuthbert D; Aoki Manabu; Hayashi Hironori; Agniswamy Johnson; Wang Yuan Fang; Bulut Haydar; Das Debananda; Weber Irene T; Mitsuya Hiroaki

来源：Journal of Medicinal Chemistry, 2017, 60(10): 4267-4278.

DOI：10.1021/acs.jmedchem.7b00172

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydro-pyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonarnide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently-in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

• 出版日期2017-5-25
• 单位NIH