title: Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.
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.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850 (China).
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Wu
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Bingjie
authors.initials: B
authors.lastname: Qin
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Chin Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006207:Half-Life; D054879:Halogenation; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D011743:Pyrimidines / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
keywords: anti-HIV activity; antiviral agents; diarylpyridinamines; drug-like properties; lipophilicity