title: Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.
abstract: The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.
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: 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: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
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: D000284:Administration, Oral; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D000882:Haplorhini; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D011759:Pyrrolidines; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C570053:sphingosine-1-phosphate receptor-2, rat; C032519:pyrrolidine
keywords: Antagonist; G protein-coupled receptors; Sphingosine-1-phosphate receptor 2