title: Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity.
abstract: We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan. imamura_shin-ichi@takeda.co.jp
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Youichi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takashima
authors.forename: Shinichi
authors.initials: S
authors.lastname: Niwa
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* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D019713:Receptors, CCR5; C506969:TAK-220