title: CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives.
abstract: Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. imamura_shin-ichi@takeda.co.jp
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.forename: Youichi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Taeko
authors.initials: T
authors.lastname: Hattori
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Shohei
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sugihara
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D019713:Receptors, CCR5 / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D019713:Receptors, CCR5