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Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.
Yu, Ming; Lizarzaburu, Mike; Motani, Alykhan; Fu, Zice; Du, Xiaohui; Liu, Jiwen Jim; Jiao, Xianyun; Lai, SuJen; Fan, Peter; Fu, Angela; Liu, Qingxiang; Murakoshi, Michiko; Nara, Futoshi; Oda, Kozo; Okuyama, Ryo; Reagan, Jeff D; Watanabe, Nobuaki; Yamazaki, Mami; Xiong, Yumei; Zhang, Ying; Zhuang, Run; Lin, Daniel C-H; Houze, Jonathan B; Medina, Julio C; Li, Leping.
Afiliación
  • Yu M; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Lizarzaburu M; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Motani A; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Fu Z; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Du X; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Liu JJ; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Jiao X; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Lai S; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Fan P; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Fu A; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Liu Q; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Murakoshi M; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Nara F; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Oda K; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Okuyama R; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Reagan JD; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Watanabe N; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Yamazaki M; Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
  • Xiong Y; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Zhang Y; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Zhuang R; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Lin DC; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Houze JB; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Medina JC; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Li L; Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
ACS Med Chem Lett ; 4(9): 829-34, 2013 Sep 12.
Article en En | MEDLINE | ID: mdl-24900757
ABSTRACT
Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos