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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.

ABSTRACT: Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing.

SUBMITTER: Christiansen E

PROVIDER: S-EPMC3654565 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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

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Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates.

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Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist.

Project description:Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation of KOR in the central nervous system (CNS) may cause sedation and anxiety. It has been reported that peripheral KOR activation produces comparable bioactivity without CNS-related side effects. Herein, we designed and synthesized a novel tetrapeptide (SHR0687), which was shown to be a highly potent KOR agonist with excellent selectivity over other opioid receptors, such as MOR and DOR. In addition, SHR0687 displayed favorable PK profiles across species, as well as robust in vivo efficacy in a rat carrageenan-induced pain model. Notably, SHR0687 exhibited negligible blood-brain barrier penetration, which was meaningful in minimizing CNS-related side effects.

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