Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6-diarylpyridinamines As a Novel Class of HIV-1 NNRTIS

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2014 Jun 5

PMID 24895029

Citations 5

Authors

Zhi-Yuan Wu

Na Liu

Bingjie Qin

Li Huang

Fei Yu

Keduo Qian

Susan L Morris-Natschke

Shibo Jiang

Chin Ho Chen

Kuo-Hsiung Lee

Lan Xie

Affiliations

Soon will be listed here.

Abstract

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10 nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.

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