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Optimization of GPR40 Agonists for Type 2 Diabetes
Jiwen Jim Liu1, Yingcai Wang1, Zhihua Ma1
1Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
ACS Medicinal Chemistry Letters
|June 6, 2014
Summary
Researchers developed novel GPR40 agonists for type 2 diabetes treatment. AM-4668 demonstrated improved potency and pharmacokinetic properties with minimal CNS penetration, offering a promising alternative drug candidate.
Area of Science:
- Pharmacology
- Endocrinology
- Medicinal Chemistry
Background:
- G protein-coupled receptor 40 (GPR40), also known as FFA1 or FFAR1, is a key target for type 2 diabetes treatment.
- Previous GPR40 agonists, like TAK-875, showed efficacy in lowering blood glucose levels in clinical trials.
- AMG 837 was identified as a clinical candidate, necessitating the search for structurally distinct backup compounds.
Purpose of the Study:
- To identify novel, structurally distinct GPR40 agonists as backup compounds for AMG 837.
- To optimize phenylpropanoic acid derivatives for enhanced GPR40 agonistic activity.
- To evaluate the potency, pharmacokinetic properties, and CNS penetration of newly identified agonists.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on phenylpropanoic acid derivatives.
- Lead compounds were optimized for GPR40 agonistic activity.
- Pharmacokinetic profiling was performed across multiple species.
- In vitro assays were used to assess potency and CNS penetration.
Main Results:
- Identification of more polar GPR40 agonists, exemplified by AM-4668.
- AM-4668 exhibited improved potency compared to previous compounds.
- The identified agonists demonstrated excellent pharmacokinetic properties.
- Compounds showed minimal central nervous system penetration.
Conclusions:
- Novel, more polar GPR40 agonists have been discovered.
- AM-4668 represents a promising backup candidate with enhanced potency and favorable pharmacokinetic profiles.
- These findings support the continued development of GPR40 agonists for type 2 diabetes therapy with reduced CNS side effects.
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