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Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS
Author(s) -
Wu ZhiYuan,
Liu Na,
Qin Bingjie,
Huang Li,
Yu Fei,
Qian Keduo,
MorrisNatschke Susan L.,
Jiang Shibo,
Chen Chin Ho,
Lee KuoHsiung,
Xie Lan
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400075
Subject(s) - lipophilicity , potency , chemistry , human immunodeficiency virus (hiv) , stereochemistry , drug , in vitro , metabolic stability , microsome , drug resistance , pharmacology , biochemistry , biology , virology , genetics
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 (EC 50 <10 n M ). 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 n M ) 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.