title: Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.
abstract: Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. Electronic address: kusumi@ono.co.jp.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kusumi
authors.affiliation: Ono Pharma UK Ltd, MidCity Place, 71 High Holborn, London WC1V 6EA, United Kingdom.
authors.forename: Koji
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Haruto
authors.initials: H
authors.lastname: Kurata
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naganawa
authors.affiliation: Head Office, Ono Pharmaceutical Co., Ltd, 8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka 541-8564, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Otsuki
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sekiguchi
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Kakuuchi
authors.affiliation: Head Office, Ono Pharmaceutical Co., Ltd, 8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka 541-8564, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Seko
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C570053:sphingosine-1-phosphate receptor-2, rat
keywords: Antagonist; G protein-coupled receptors; Metabolic stability; Sphingosine-1-phosphate receptor 2