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Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.
Wang, Yingcai; Liu, Jiwen Jim; Dransfield, Paul J; Zhu, Liusheng; Wang, Zhongyu; Du, Xiaohui; Jiao, Xianyun; Su, Yongli; Li, An-Rong; Brown, Sean P; Kasparian, Annie; Vimolratana, Marc; Yu, Ming; Pattaropong, Vatee; Houze, Jonathan B; Swaminath, Gayathri; Tran, Thanhvien; Nguyen, Khanh; Guo, Qi; Zhang, Jane; Zhuang, Run; Li, Frank; Miao, Lynn; Bartberger, Michael D; Correll, Tiffany L; Chow, David; Wong, Simon; Luo, Jian; Lin, Daniel C-H; Medina, Julio C.
Affiliation
  • Wang Y; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Liu JJ; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Dransfield PJ; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Zhu L; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Wang Z; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Du X; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Jiao X; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Su Y; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Li AR; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Brown SP; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Kasparian A; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Vimolratana M; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Yu M; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Pattaropong V; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Houze JB; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Swaminath G; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Tran T; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Nguyen K; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Guo Q; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Zhang J; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Zhuang R; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Li F; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Miao L; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Bartberger MD; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Correll TL; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Chow D; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Wong S; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Luo J; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Lin DC; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Medina JC; Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
ACS Med Chem Lett ; 4(6): 551-5, 2013 Jun 13.
Article in En | MEDLINE | ID: mdl-24900707
GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2013 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2013 Document type: Article Affiliation country: United States Country of publication: United States