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    • zotarolimus Having shown that some of substitutions Cl CF at

    2021-10-20

    Having shown that some of substitutions (Cl, CF) at the 2-position of the thiophene improved rat microsomal stability, and polar groups at the 4-position of the aryl ring had a beneficial effect on stability in both human and rat microsomes, we combined these features in a new set of analogs. Methyl (), fluoro (), and chloro () substitution at the 2-position of the benzo[]thiophene further improves the human microsomal stability of , but with a 3- to 8-fold loss of GPR40 potency (). However, trifluoromethyl () substitution not only maintained good GPR40 activity, but also greatly increased microsomal stability in both species, with T greater than 3 h. Several compounds were selected for pharmacokinetic (PK) profiling in rat (). As expected from its low microsomal stability in rat, has high clearance and low oral exposure. Fluorination of the benzo[]thiophene ring () led to a 3-fold increase with respect to oral exposure, but the clearance was still high. Both 2-chloro-benzo[]thiophene () and 2-trifluoromethyl-benzo[]thiophene () showed low clearance and higher oral exposure, consistent with their relatively good stability in rat microsomes. Despite that the sulfone-containing compounds, and had good microsomal stability in human and rat, their rat PK profiles are not optimal, with very high clearance and low oral exposure. It is worth mentioning that the molecular weights of and are 601 and 613, respectively, which may be one of the contributing factors to their poor PK profiles. We did not run rat PK on the optimized zotarolimus . Instead it was tested directly for pharmacological activity with measurement of oral exposure, which will be discussed later. Compound was selected for an evaluation based on its good rGPR40 activity (EC = 5 nM) and acceptable T (2.5 h) for oral dosing. Oral administration of in normal Sprague Dawley (SD) rats 40 min prior to glucose challenge in an oral glucose tolerance test (oGTT) significantly reduced blood glucose excursion in a dose-dependent manner (). At a dose of 10 mg/kg, demonstrated comparable efficacy to TAK-875 with a much lower exposure (1.85 ± 0.80 μM) than TAK-875 (35.3 ± 7.6 μM). Several other optimized compounds were also tested in oGTT studies. lists the efficacy of these compounds in terms of total AUC (area under curve) percentage changes vs. vehicle, which measures the compound’s ability to lower blood glucose excursion within 2 h post oral glucose challenge. The concentrations of the compounds in plasma taken 160 min after compound dose are also shown here. Derived from , the total AUC % change vs vehicle for is −8.3 and −19 at the 1 mg/kg dose and 10 mg/kg dose, respectively. With a similar PK profile as , is also efficacious at the oGTT model at a dose of 10 mg/kg. Surprisingly, compounds with low clearance and higher oral exposure in PK, such as and , are slightly less potent despite higher compound concentrations, which may be explained by the 3–4-fold potency difference. There seems to be no correlation between PK profile and efficacy. Therefore, the metabolically stable was tested directly with a 3-time point measurement of plasma concentrations. Even though there is moderate amount of compound measured at all three time points, is less efficacious than at lowering blood glucose in the oGTT assay. In conclusion, a series of tetrazoles with a benzo[]thiophene center ring were discovered as non-carboxylate GPR40 agonists. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for evaluation. However, there was a disconnect between compound exposure level and pharmacodynamic efficacy. Various reasons could contribute to this phenomenon. For instance, high plasma protein binding may result in less drug available to the target tissue. Unfortunately, our effort to obtain rat plasma protein binding data for the compounds failed due to their extremely long equilibration times and high non-specific binding to the equilibrium dialysis device. Nevertheless, tetrazole has shown good efficacy at lowering blood glucose in Sprague-Dawley rats even at a low exposure. We have demonstrated that non-carboxylate GPR40 agonists have the potential to be next generation glucose lowering agents without the risk of forming potentially toxic AG metabolites.