Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

Abstract

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp/sp character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

Leveraging the Gut to Treat Metabolic Disease

“…oral QD Phase 1 (discontinued) T2DM (Chen et al, 2016;Hamdouchi et al, 2016) MK-8666 oral QD Phase 1 (discontinued) T2DM (Krug et al, 2017;Lu et al, 2017) Putative gut peptide secretagogues with preclinical data only GPR40 full agonists AMG-1638; AM-6226 N/A Preclinical T2DM (Brown et al, 2012;Luo et al, 2012) BMS-986118 N/A Preclinical T2DM (Shi et al, 2018) Cpd 12 N/A Preclinical T2DM (Meegalla et al, 2018) AP1; AP3 N/A Preclinical T2DM (Pachanski et al, 2017) GPR120 agonists TUG-891 N/A Preclinical T2DM (Schilperoort et al, 2018) Cpd 4x N/A Preclinical T2DM (Zhang et al, 2017) Cpd 34 N/A Preclinical T2DM (Azevedo et al, 2016) TGR5 agonists INT-777 N/A Preclinical T2DM (Pellicciari et al, 2009;Li et al, 2011) Cpd 18 N/A Preclinical T2DM (Briere et al, 2015) GPR142 agonists Cpd 33; Cpd 23 N/A Preclinical T2DM (Toda et al, 2013;Yu et al, 2013) Cpd 40 N/A Preclinical T2DM (Wilson et al, 2016) GPR39 agonists Cpd 3 N/A Preclinical T2DM (Peukert et al, 2014) SSTR5 antagonists S5A1 N/A Preclinical T2DM (Farb et al, 2017) Cpd 10 N/A Preclinical T2DM (Liu et al, 2018) Cpd 25a N/A Preclinical T2DM (Hirose et al, 2017) Molecules on the market or in active clinical development; discontinued molecules included if published information available. Select preclinical molecules included for mechanisms that have not progressed to the clinic to date.…”

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…This compound maintained the potency and selectivity profile of 104b while exhibiting a lower propensity to form GSH adducts in liver microsomal preparations. Compound 104c exhibited insulinotropic efficacy and GLP-1 secretory effects that translated into improved glucose control in animal models of acute disease …”

Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

“…The long-term effects of untreated high blood sugar can be severe and may include reduced cardiac function (heart disease) as well as blindness, kidney failure, and poor circulation. The need to aid the large population of individuals suffering from this disease is a driver to develop better treatments, and our Discovery Chemistry colleagues identified 1 (Scheme ) as a lead molecule that is a potent agonist of the GPR40 receptor . Compound 1 was found to promote both gut peptide and glucose-dependent insulin secretion in a variety of animal models, and >1 kg of material was required to allow for a more thorough toxicology evaluation.…”