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Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.
Kusumi, Kensuke; Shinozaki, Koji; Yamaura, Yoshiyuki; Hashimoto, Ai; Kurata, Haruto; Naganawa, Atsushi; Otsuki, Kazuhiro; Matsushita, Takeshi; Sekiguchi, Tetsuya; Kakuuchi, Akito; Yamamoto, Hiroshi; Seko, Takuya.
  • Kusumi K; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. Electronic address: kusumi@ono.co.jp.
  • Shinozaki K; Ono Pharma UK Ltd, MidCity Place, 71 High Holborn, London WC1V 6EA, United Kingdom.
  • Yamaura Y; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Hashimoto A; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Kurata H; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Naganawa A; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Otsuki K; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Matsushita T; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Sekiguchi T; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Kakuuchi A; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Yamamoto H; Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • Seko T; Head Office, Ono Pharmaceutical Co., Ltd, 8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka 541-8564, Japan.
Bioorg Med Chem Lett ; 26(4): 1209-13, 2016 Feb 15.
Article en En | MEDLINE | ID: mdl-26794040
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Derivados del Benceno / Receptores de Lisoesfingolípidos Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Derivados del Benceno / Receptores de Lisoesfingolípidos Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article