Improving the pharmacokinetics of GPR40/FFA1 full agonists

Xiaohui Du; Paul J. Dransfield; Daniel C.H. Lin; Simon Wong; Yingcai Wang; Zhongyu Wang; Todd Kohn; Ming Yu; Sean P. Brown; Marc Vimolratana; Liusheng Zhu; An Rong Li; Yongli Su; Xianyun Jiao; Jiwen Liu; Gayathri Swaminath; Thanhvien Tran; Jian Luo; Run Zhuang; Jane Zhang; Qi Guo; Frank Li; Richard Connors; Julio C. Medina; Jonathan B. Houze

doi:10.1021/ml4005123

Improving the pharmacokinetics of GPR40/FFA1 full agonists

Xiaohui Du, Paul J. Dransfield, Daniel C.H. Lin, Simon Wong, Yingcai Wang, Zhongyu Wang, Todd Kohn, Ming Yu, Sean P. Brown, Marc Vimolratana, Liusheng Zhu, An Rong Li, Yongli Su, Xianyun Jiao, Jiwen Liu, Gayathri Swaminath, Thanhvien Tran, Jian Luo, Run Zhuang, Jane ZhangQi Guo, Frank Li, Richard Connors, Julio C. Medina, Jonathan B. Houze

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

25 Scopus citations

Abstract

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

Original language	English (US)
Pages (from-to)	384-389
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	4
DOIs	https://doi.org/10.1021/ml4005123
State	Published - Apr 10 2014
Externally published	Yes

Keywords

FFA1
GPR40
full agonist
insulin secretagoue
type 2 diabetes

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/ml4005123

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Du, X., Dransfield, P. J., Lin, D. C. H., Wong, S., Wang, Y., Wang, Z., Kohn, T., Yu, M., Brown, S. P., Vimolratana, M., Zhu, L., Li, A. R., Su, Y., Jiao, X., Liu, J., Swaminath, G., Tran, T., Luo, J., Zhuang, R., ... Houze, J. B. (2014). Improving the pharmacokinetics of GPR40/FFA1 full agonists. ACS Medicinal Chemistry Letters, 5(4), 384-389. https://doi.org/10.1021/ml4005123

Du, X, Dransfield, PJ, Lin, DCH, Wong, S, Wang, Y, Wang, Z, Kohn, T, Yu, M, Brown, SP, Vimolratana, M, Zhu, L, Li, AR, Su, Y, Jiao, X, Liu, J, Swaminath, G, Tran, T, Luo, J, Zhuang, R, Zhang, J, Guo, Q, Li, F, Connors, R, Medina, JC & Houze, JB 2014, 'Improving the pharmacokinetics of GPR40/FFA1 full agonists', ACS Medicinal Chemistry Letters, vol. 5, no. 4, pp. 384-389. https://doi.org/10.1021/ml4005123

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title = "Improving the pharmacokinetics of GPR40/FFA1 full agonists",

abstract = "We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.",

keywords = "FFA1, GPR40, full agonist, insulin secretagoue, type 2 diabetes",

author = "Xiaohui Du and Dransfield, {Paul J.} and Lin, {Daniel C.H.} and Simon Wong and Yingcai Wang and Zhongyu Wang and Todd Kohn and Ming Yu and Brown, {Sean P.} and Marc Vimolratana and Liusheng Zhu and Li, {An Rong} and Yongli Su and Xianyun Jiao and Jiwen Liu and Gayathri Swaminath and Thanhvien Tran and Jian Luo and Run Zhuang and Jane Zhang and Qi Guo and Frank Li and Richard Connors and Medina, {Julio C.} and Houze, {Jonathan B.}",

year = "2014",

month = apr,

day = "10",

doi = "10.1021/ml4005123",

language = "English (US)",

volume = "5",

pages = "384--389",

journal = "ACS Medicinal Chemistry Letters",

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publisher = "American Chemical Society",

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T1 - Improving the pharmacokinetics of GPR40/FFA1 full agonists

AU - Du, Xiaohui

AU - Dransfield, Paul J.

AU - Lin, Daniel C.H.

AU - Wong, Simon

AU - Wang, Yingcai

AU - Wang, Zhongyu

AU - Kohn, Todd

AU - Yu, Ming

AU - Brown, Sean P.

AU - Vimolratana, Marc

AU - Zhu, Liusheng

AU - Li, An Rong

AU - Su, Yongli

AU - Jiao, Xianyun

AU - Liu, Jiwen

AU - Swaminath, Gayathri

AU - Tran, Thanhvien

AU - Luo, Jian

AU - Zhuang, Run

AU - Zhang, Jane

AU - Guo, Qi

AU - Li, Frank

AU - Connors, Richard

AU - Medina, Julio C.

AU - Houze, Jonathan B.

PY - 2014/4/10

Y1 - 2014/4/10

N2 - We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

AB - We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

KW - FFA1

KW - GPR40

KW - full agonist

KW - insulin secretagoue

KW - type 2 diabetes

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JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -

Improving the pharmacokinetics of GPR40/FFA1 full agonists

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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