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Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

Authors :
Ding, Li
Pannecouque, Christophe
De Clercq, Erik
Zhuang, Chunlin
Chen, Fen-Er
Source :
Journal of Medicinal Chemistry; February 2022, Vol. 65 Issue: 3 p2122-2138, 17p
Publication Year :
2022

Abstract

A series of novel heteroaromatic biphenyl-methyl-pyrimidine analogues were designed via hybridization of privileged structures of two HIV-1 inhibitors. Among them, compound 7acontaining 4-pyridinyl-phenyl and methyl-pyrimidine fragments revealed excellent wild-type HIV-1 inhibitory activity with low cytotoxicity. 7ahad favorable solubility and liver microsome stability; moreover, no apparent CYP enzymatic inhibitory activity or acute toxicity was observed. However, its inhibitory activity toward mutant strains and the pharmacokinetic (PK) profiles were still unsatisfactory. Further optimizations resulted in a highly potent compound 9dwithout methyl on the pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum activity (EC50= 2.0–57 nM) of 9dagainst resistant strains was revealed. This compound also exhibited good solubility and safety profiles and a good PK profile with an oral bioavailability of 59% in rats. Collectively, these novel heteroaromatic dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.

Details

Language :
English
ISSN :
00222623 and 15204804
Volume :
65
Issue :
3
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs58748027
Full Text :
https://doi.org/10.1021/acs.jmedchem.1c01676