Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

Yingcai Wang; Jiwen Liu; Paul J. Dransfield; Liusheng Zhu; Zhongyu Wang; Xiaohui Du; Xianyun Jiao; Yongli Su; An Rong Li; Sean P. Brown; Annie Kasparian; Marc Vimolratana; Ming Yu; Vatee Pattaropong; Jonathan B. Houze; Gayathri Swaminath; Thanhvien Tran; Khanh Nguyen; Qi Guo; Jane Zhang; Run Zhuang; Frank Li; Lynn Miao; Michael D. Bartberger; Tiffany L. Correll; David Chow; Simon Wong; Jian Luo; Daniel C.H. Lin; Julio C. Medina

doi:10.1021/ml300427u

Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

Yingcai Wang, Jiwen Liu, Paul J. Dransfield, Liusheng Zhu, Zhongyu Wang, Xiaohui Du, Xianyun Jiao, Yongli Su, An Rong Li, Sean P. Brown, Annie Kasparian, Marc Vimolratana, Ming Yu, Vatee Pattaropong, Jonathan B. Houze, Gayathri Swaminath, Thanhvien Tran, Khanh Nguyen, Qi Guo, Jane ZhangRun Zhuang, Frank Li, Lynn Miao, Michael D. Bartberger, Tiffany L. Correll, David Chow, Simon Wong, Jian Luo, Daniel C.H. Lin, Julio C. Medina

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

74 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	551-555
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	6
DOIs	https://doi.org/10.1021/ml300427u
State	Published - Jun 13 2013
Externally published	Yes

Keywords

AM-1638
AM-5262
AMG 837
FFA1
FFAR1
Full agonist
GPR40
Spirocycles
Tricyclic

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/ml300427u

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Wang, Y., Liu, J., Dransfield, P. J., Zhu, L., Wang, Z., Du, X., Jiao, X., Su, Y., Li, A. R., Brown, S. P., Kasparian, A., Vimolratana, M., Yu, M., Pattaropong, V., Houze, J. B., Swaminath, G., Tran, T., Nguyen, K., Guo, Q., ... Medina, J. C. (2013). Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles. ACS Medicinal Chemistry Letters, 4(6), 551-555. https://doi.org/10.1021/ml300427u

Wang, Y, Liu, J, Dransfield, PJ, Zhu, L, Wang, Z, Du, X, Jiao, X, Su, Y, Li, AR, Brown, SP, Kasparian, A, Vimolratana, M, Yu, M, Pattaropong, V, Houze, JB, Swaminath, G, Tran, T, Nguyen, K, Guo, Q, Zhang, J, Zhuang, R, Li, F, Miao, L, Bartberger, MD, Correll, TL, Chow, D, Wong, S, Luo, J, Lin, DCH & Medina, JC 2013, 'Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles', ACS Medicinal Chemistry Letters, vol. 4, no. 6, pp. 551-555. https://doi.org/10.1021/ml300427u

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title = "Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles",

abstract = "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.",

keywords = "AM-1638, AM-5262, AMG 837, FFA1, FFAR1, Full agonist, GPR40, Spirocycles, Tricyclic",

author = "Yingcai Wang and Jiwen Liu and Dransfield, {Paul J.} and Liusheng Zhu and Zhongyu Wang and Xiaohui Du and Xianyun Jiao and Yongli Su and Li, {An Rong} and Brown, {Sean P.} and Annie Kasparian and Marc Vimolratana and Ming Yu and Vatee Pattaropong and Houze, {Jonathan B.} and Gayathri Swaminath and Thanhvien Tran and Khanh Nguyen and Qi Guo and Jane Zhang and Run Zhuang and Frank Li and Lynn Miao and Bartberger, {Michael D.} and Correll, {Tiffany L.} and David Chow and Simon Wong and Jian Luo and Lin, {Daniel C.H.} and Medina, {Julio C.}",

year = "2013",

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doi = "10.1021/ml300427u",

language = "English (US)",

volume = "4",

pages = "551--555",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

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T1 - Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

AU - Wang, Yingcai

AU - Liu, Jiwen

AU - Dransfield, Paul J.

AU - Zhu, Liusheng

AU - Wang, Zhongyu

AU - Du, Xiaohui

AU - Jiao, Xianyun

AU - Su, Yongli

AU - Li, An Rong

AU - Brown, Sean P.

AU - Kasparian, Annie

AU - Vimolratana, Marc

AU - Yu, Ming

AU - Pattaropong, Vatee

AU - Houze, Jonathan B.

AU - Swaminath, Gayathri

AU - Tran, Thanhvien

AU - Nguyen, Khanh

AU - Guo, Qi

AU - Zhang, Jane

AU - Zhuang, Run

AU - Li, Frank

AU - Miao, Lynn

AU - Bartberger, Michael D.

AU - Correll, Tiffany L.

AU - Chow, David

AU - Wong, Simon

AU - Luo, Jian

AU - Lin, Daniel C.H.

AU - Medina, Julio C.

PY - 2013/6/13

Y1 - 2013/6/13

N2 - 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.

AB - 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.

KW - AM-1638

KW - AM-5262

KW - AMG 837

KW - FFA1

KW - FFAR1

KW - Full agonist

KW - GPR40

KW - Spirocycles

KW - Tricyclic

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JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 6

ER -

Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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