Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist

Sean P. Brown; Paul J. Dransfield; Marc Vimolratana; Xianyun Jiao; Liusheng Zhu; Vatee Pattaropong; Ying Sun; Jinqian Liu; Jian Luo; Jane Zhang; Simon Wong; Run Zhuang; Qi Guo; Frank Li; Julio C. Medina; Gayathri Swaminath; Daniel C.H. Lin; Jonathan B. Houze

doi:10.1021/ml300133f

Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist

Sean P. Brown, Paul J. Dransfield, Marc Vimolratana, Xianyun Jiao, Liusheng Zhu, Vatee Pattaropong, Ying Sun, Jinqian Liu, Jian Luo, Jane Zhang, Simon Wong, Run Zhuang, Qi Guo, Frank Li, Julio C. Medina, Gayathri Swaminath, Daniel C.H. Lin, Jonathan B. Houze

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

83 Scopus citations

Abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

Original language	English (US)
Pages (from-to)	726-730
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	9
DOIs	https://doi.org/10.1021/ml300133f
State	Published - Sep 13 2012
Externally published	Yes

Keywords

AM-1638
AMG 837
FFA1
GPR40
full agonist
insulin secretagogue

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml300133f

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Brown, S. P., Dransfield, P. J., Vimolratana, M., Jiao, X., Zhu, L., Pattaropong, V., Sun, Y., Liu, J., Luo, J., Zhang, J., Wong, S., Zhuang, R., Guo, Q., Li, F., Medina, J. C., Swaminath, G., Lin, D. C. H., & Houze, J. B. (2012). Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist. ACS Medicinal Chemistry Letters, 3(9), 726-730. https://doi.org/10.1021/ml300133f

Brown, SP, Dransfield, PJ, Vimolratana, M, Jiao, X, Zhu, L, Pattaropong, V, Sun, Y, Liu, J, Luo, J, Zhang, J, Wong, S, Zhuang, R, Guo, Q, Li, F, Medina, JC, Swaminath, G, Lin, DCH & Houze, JB 2012, 'Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist', ACS Medicinal Chemistry Letters, vol. 3, no. 9, pp. 726-730. https://doi.org/10.1021/ml300133f

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title = "Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist",

abstract = "GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.",

keywords = "AM-1638, AMG 837, FFA1, GPR40, full agonist, insulin secretagogue",

author = "Brown, {Sean P.} and Dransfield, {Paul J.} and Marc Vimolratana and Xianyun Jiao and Liusheng Zhu and Vatee Pattaropong and Ying Sun and Jinqian Liu and Jian Luo and Jane Zhang and Simon Wong and Run Zhuang and Qi Guo and Frank Li and Medina, {Julio C.} and Gayathri Swaminath and Lin, {Daniel C.H.} and Houze, {Jonathan B.}",

year = "2012",

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doi = "10.1021/ml300133f",

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AU - Vimolratana, Marc

AU - Jiao, Xianyun

AU - Zhu, Liusheng

AU - Pattaropong, Vatee

AU - Sun, Ying

AU - Liu, Jinqian

AU - Luo, Jian

AU - Zhang, Jane

AU - Wong, Simon

AU - Zhuang, Run

AU - Guo, Qi

AU - Li, Frank

AU - Medina, Julio C.

AU - Swaminath, Gayathri

AU - Lin, Daniel C.H.

AU - Houze, Jonathan B.

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AB - GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

KW - AM-1638

KW - AMG 837

KW - FFA1

KW - GPR40

KW - full agonist

KW - insulin secretagogue

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Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist

Abstract

Keywords

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