Recently they reported an enyne chemotype agonist Fig with

Recently, they reported an enyne chemotype agonist (21, Fig. 13) with low lipophilicity, small polar surface area (PSA) and high potency (Clog P=3.8, tPSA=37 A2, EC50=20nM), further derived from TUG-424. The compound endowed fast oral Probenecid mg (tmax=15min) and a decent pharmacokinetic profile, a satisfactory plasma half-life (t1/2=1.5h), moderate clearance and good overall exposure. A significant glucose lowering effect and increased insulin response were observed following oral dosing at 10mg/kg [56]. Improving the selectivity: It is well recognized that improving the selectivity of the drug candidates can reduce the adverse effect or toxicity and enhance the safety. Selectivity is also an important factor for GPR40 agonists since it is expressed in pancreas and brain. Furthermore, improving the selectivity can be helpful to address the hepatotoxicity issue of TAK-875. Many pharmaceutical companies have made great efforts to boost the selectivity of GPR40 agonists. For example, Eli Lilly improved the compounds’ selectivity over PPARγ by using polar fragments. Amgen and Daiichi Sankyo promoted the selectivity by conformational constraining. Amgen is one of the earliest companies to initiate GPR40-based therapy research, and AMG 837 (Fig. 14) was the first GPR40 agonist to enter clinical trials [57]. AMG 837 displayed high potency (EC50=13nM) in the Ca2+ flux assay and high functional activity in a mouse β-cell line (MIN6). It also possessed high selectivity over the closely related GPCRs such as GPR41 and GPR43. The pharmacokinetic profile of AMG 837 was excellent in multiple species. Low clearance (0.06–0.08L/h/kg), long half-life (7.2–28h), and high oral bioavailability (67–100%) were observed in four preclinical species, i.e. mouse, rat, dog and monkey. AMG-837 induced significantly lowering glucose level in OGTT in wild type mice, while not in GPR40 knock-out mice [14]. However, high lipophilicity and low PSA may cause central nervous system penetration. Correspondingly, the researchers tried to address this issue by replacing the propynal and the biphenyl group of AMG 837 with a polar isoxazol and phenyl-thiazol moiety, respectively, delivering AMG-4668 with improved potency (EC50=36nM), excellent pharmacokinetic properties and minimum CNS penetration (Fig. 14) [58]. Imidazole group was also used to replace the propynal substituent, yielding AM-3189 (Fig. 14) with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837[59]. In 2012, Amgen communicated the development of GPR40 full agonists. Firstly they switched the stereochemistry at the β-position and relocated the biphenyl linkage from the 3- to 4-position of AMG 837 to generate AMG-8596 (Fig. 14) [12]. It was found to demonstrate desired properties of full agonist (EC50=3.8μM, Emax=98%), while its isomer was partial agonist (EC50=0.65μM, Emax=30%). Then, AMG-8596 was optimized by an exchange of the propinyl group with a cyclopropane, relocation of the ether linkage from a para to an ortho-orientation on the central phenyl ring and addition of a 5,5-dimethylcyclopent-1-enyl group to the biphenyl moiety to bring about a potent full agonist AM-1638 (EC50=0.166μM, Emax=100%) (Fig. 14) [12]. To increase the polarity, nitrogen was introduced into phenyl ring to give 22 (Fig. 14) [58]. Meanwhile, further conformational constraining of phenylpropionic acid on AM-1638 resulted in the discovery of tricyclic spirocycle AM-5262 (EC50=81nM, Emax=105%), with improved rat PK profile and general selectivity profile (Fig. 14) [13]. AM-5262 bound to the same ligand site on GPR40 as AM-1638 and enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) [12], [13]. As mentioned above, as GPR40 full agonists, AM-1638 and AM-5262 can stimulate insulin incretion via both Gq and Gs pathways. Compared to AMG 837, AM-1638 and AM-5262 can activate GPR40 on the intestinal cells simultaneously, increase GLP-1 and GIP levels in vivo and express greater efficacy on insulin secretion and glucose reduction [12], [13].