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Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469.

ABSTRACT: The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).

SUBMITTER: Christiansen E

PROVIDER: S-EPMC4007913 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes.

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Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.

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Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist.

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Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.

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Project description: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.

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Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency.

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GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40).

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