title: Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist.
abstract: Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
authors.affiliation: Medicinal Chemistry Research Laboratory, Ono Pharmaceutical Co. Ltd, Shimamoto, Mishima, Osaka, Japan. r.nishizawa@ono.co.jp
authors.forename: Rena
authors.initials: R
authors.lastname: Nishizawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hisaichi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Minamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Murota
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tada
authors.forename: Kenji
authors.initials: K
authors.lastname: Sagawa
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
authors.forename: Daikichi
authors.initials: D
authors.lastname: Fukushima
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D011817:Rabbits; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C561761:4-(4-((1-butyl-3-(cyclohexyl(hydroxy)methyl)-2,5-dioxo-1,4,9-triazaspiro(5.5)undec-9-yl)methyl)phenoxy)benzoic acid; D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D019713:Receptors, CCR5