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. 2014 Feb 3;5(4):384-9.
doi: 10.1021/ml4005123. eCollection 2014 Apr 10.

Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

Xiaohui Du  1 , Paul J Dransfield  1 , Daniel C-H Lin  1 , Simon Wong  1 , Yingcai Wang  1 , Zhongyu Wang  1 , Todd Kohn  1 , Ming Yu  1 , Sean P Brown  1 , Marc Vimolratana  1 , Liusheng Zhu  1 , An-Rong Li  1 , Yongli Su  1 , Xianyun Jiao  1 , Jiwen Jim Liu  1 , Gayathri Swaminath  1 , Thanhvien Tran  1 , Jian Luo  1 , Run Zhuang  1 , Jane Zhang  1 , Qi Guo  1 , Frank Li  1 , Richard Connors  1 , Julio C Medina  1 , Jonathan B Houze  1
Affiliations

Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

Xiaohui Du et al. ACS Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
GPR40 full agonist AM-1638 (1).
Figure 2
Figure 2
In vivo results of dosing compound 8 in a HF/STZ type II diabetic model in mice. Compound 8 lowered blood glucose in a dose-dependent manner. Statistical significance compared to vehicle treatment is denoted by *(p < 0.05), **(p < 0.01), ***(p < 0.001), and ****(p < 0.0001), as determined by two-way ANOVA, and is color-coded to the treatment in the figure legends.
Scheme 1
Scheme 1
Figure 3
Figure 3
Compound 20 showed glucose-lowering effect in a BDF-DIO model in mice. Statistical significance compared to vehicle treatment is denoted by *(p < 0.05), **(p < 0.01), ***(p < 0.001), and ****(p < 0.0001), as determined by two-way ANOVA, and is color-coded to the treatment in the figure legends.
See this image and copyright information in PMC

References

    1. Defronzo R. A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes. Diabetes 2009, 58, 773–795. - PMC - PubMed
    1. Nazimek-Siewniak B.; Moczulski D.; Grzeszczak W. Risk of macrovascular and microvascular complications in Type 2 diabetes: results of longitudinal study design. J. Diabetes Complications 2002, 16, 271–276. - PubMed
    1. Kles K. A.; Vinik A. I. Pathophysiology and treatment of diabetic peripheral neuropathy: the case for diabetic neurovascular function as an essential component. Curr. Diabetes Rev. 2006, 2, 131–145. - PubMed
    1. Rahman S.; Rahman T.; Ismail A. A.; Rashid A. R. Diabetes-associated macrovasculopathy: pathophysiology and pathogenesis. Diabetes Obes. Metab. 2007, 9, 767–780. - PubMed
    1. Edfalk S.; Steneberg P.; Edlund H. GPR40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 2008, 57, 2280–2287. - PMC - PubMed