Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency Against Multidrug-Resistant HIV-1 Variants

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2018 Feb 14

PMID 29437300

Citations 28

Authors

Arun K Ghosh

Kalapala Venkateswara Rao

Prasanth R Nyalapatla

Satish Kovela

Margherita Brindisi

Heather L Osswald

Bhavanam Sekhara Reddy

Johnson Agniswamy

Yuan-Fang Wang

Manabu Aoki

Shin-Ichiro Hattori

Irene T Weber

Hiroaki Mitsuya

Affiliations

Soon will be listed here.

Abstract

Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.

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