title: Discovery of orally available spirodiketopiperazine-based CCR5 antagonists.
abstract: Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, 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: Keisuke
authors.initials: K
authors.lastname: Hirai
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takaoka
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: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Daikichi
authors.initials: D
authors.lastname: Fukushima
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D018938:Caco-2 Cells; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D019713:Receptors, CCR5