Discovery of a novel potent GPR40 full agonist

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.…”

Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination

“…By incorporating N atoms to the B and C phenyl rings and simplifying the bulky alkyl substitution on the B ring, we identified our first-generation GPR40 full agonists, as represented by 7 (Figure ). The dimethylcyclopentenyl group on AM-1638 is important for its potency, however, we found that it may be replaced with small alkyl groups ( 7 ) and may even be removed when the middle aromatic ring is changed to a saturated cyclohexyl ring, like the trans -cyclohexyl compound 8 .…”