title: Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors.
abstract: A series of novel 1,4-disubstituted piperidine/piperazine derivatives were designed, synthesized and evaluated for their in vitro activities against HIV-1 Bal (R5) infection in CEMX174 5.25M7 cells. A majority of these compounds showed potent anti-HIV-1 activities with IC(50) at nanomolar levels. N-(4-Fluoro-benzyl)piperazine analog B07 hydrochloride exhibited potency against HIV-1 activity similar to that of TAK-220 hydrochloride, but it had much better water solubility (25 mg/ml in phosphate sodium buffer at 25 °C) and oral bioavailability (56%) than TAK-220 hydrochloride (a solubility of 2 mg/ml and oral bioavailability of 1.4%). These results suggest that B07 hydrochloride may serve as a better lead for the development of new anti-HIV-1 therapies or microbicides for treatment and prevent of HIV-1 infection.
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Ming-xin
authors.initials: MX
authors.lastname: Dong
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Qiu-yun
authors.initials: QY
authors.lastname: Dai
mesh_terms: D000818:Animals; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D015195:Drug Design; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D010880:Piperidines; C506969:TAK-220