title: CCR5 antagonists as anti-HIV-1 agents. Part 2: Synthesis and biological evaluation of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylureas.
abstract: We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the discovery of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylurea (4a) with significantly improved CCR5 binding affinity. Substitutions (4-Cl, 4e,f; 4-Me, 4i) on the N'-phenyl ring further increased the binding affinity. Introduction of polar substituents on the phenyl ring of the 4-benzylpiperidine moiety enhanced the inhibitory activity of the HIV-1 envelope-mediated membrane fusion (4v,w), suggesting that polar substituents at this position can interfere effectively with HIV-1 cell entry.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, 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: Osamu
authors.initials: O
authors.lastname: Kurasawa
authors.forename: Yoshi
authors.initials: Y
authors.lastname: Nara
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Youichi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Takehiro
authors.initials: T
authors.lastname: Iida
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 / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002224:Carbanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D002224:Carbanilides