Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Sean P. Brown; Paul Dransfield; Marc Vimolratana; Liusheng Zhu; Jian Luo; Jane Zhang; Xianyun Jiao; Vatee Pattaropong; Simon Wong; Run Zhuang; Gayathri Swaminath; Jonathan B. Houze; Daniel C.H. Lin

doi:10.1021/acsmedchemlett.8b00213

Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Sean P. Brown, Paul Dransfield, Marc Vimolratana, Liusheng Zhu, Jian Luo, Jane Zhang, Xianyun Jiao, Vatee Pattaropong, Simon Wong, Run Zhuang, Gayathri Swaminath, Jonathan B. Houze, Daniel C.H. Lin

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

Original language	English (US)
Pages (from-to)	757-760
Number of pages	4
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00213
State	Published - Jul 12 2018
Externally published	Yes

Keywords

AM-1638
AM-6226
AMG 837
FFA1
GPR40
full agonist
insulin secretagogue

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.8b00213

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Brown, S. P., Dransfield, P., Vimolratana, M., Zhu, L., Luo, J., Zhang, J., Jiao, X., Pattaropong, V., Wong, S., Zhuang, R., Swaminath, G., Houze, J. B., & Lin, D. C. H. (2018). Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates. ACS Medicinal Chemistry Letters, 9(7), 757-760. https://doi.org/10.1021/acsmedchemlett.8b00213

Brown, SP, Dransfield, P, Vimolratana, M, Zhu, L, Luo, J, Zhang, J, Jiao, X, Pattaropong, V, Wong, S, Zhuang, R, Swaminath, G, Houze, JB & Lin, DCH 2018, 'Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates', ACS Medicinal Chemistry Letters, vol. 9, no. 7, pp. 757-760. https://doi.org/10.1021/acsmedchemlett.8b00213

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title = "Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates",

abstract = "GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.",

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AU - Vimolratana, Marc

AU - Zhu, Liusheng

AU - Luo, Jian

AU - Zhang, Jane

AU - Jiao, Xianyun

AU - Pattaropong, Vatee

AU - Wong, Simon

AU - Zhuang, Run

AU - Swaminath, Gayathri

AU - Houze, Jonathan B.

AU - Lin, Daniel C.H.

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Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates

Abstract

Keywords

ASJC Scopus subject areas

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