2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2011 Jul 1;19(13):4028-42. doi: 10.1016/j.bmc.2011.05.022.
Rena Nishizawa 1,  Toshihiko Nishiyama,  Katsuya Hisaichi,  Chiaki Minamoto,  Masayuki Murota,  Yoshikazu Takaoka,  Hisao Nakai,  Hideaki Tada,  Kenji Sagawa,  Shiro Shibayama,  Daikichi Fukushima,  Kenji Maeda,  Hiroaki Mitsuya
Affiliations

Affiliation

  • 1 Medicinal Chemistry Research Laboratory, Ono Pharmaceutical Co. Ltd, Shimamoto, Mishima, Osaka, Japan. r.nishizawa@ono.co.jp
PMID: 21658961 DOI: 10.1016/j.bmc.2011.05.022
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.

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