Since we were able to reach low

Since we were able to reach low micromolar to sub-micromolar potency in both compound series (6 and 7), we were also keen on assessing the preliminary ADME profile (particularly with respect to plasma and liver microsomal stability) of the most active compounds from these series. As it is evident from Table 3, all compounds demonstrated very favorable octanol–water distribution properties (LogD measured at pH 7.4) which were well within the limits of established for developable drug candidates. However, the metabolic and plasma stability of the two series differed significantly: compounds 6a and 6c displayed excellent stability (in line with our previous findings) while compounds 7c and 7l were markedly unstable. This even hindered the determination of plasma protein binding for 7c, while the other three compounds displayed a good free fraction in plasma. The latter unfortunate aspect (which could be related to the presence of metabolically prone 4-phenoxy-1,2,4-thiadiazole linkage in 7a–l) will undoubtedly affect the prospects of developing compounds belonging to series 7 as pharmacological tools or drug candidates. The four lead compounds (6a, 6c, 7c, 7l) displayed very favorable hERG binding profile as determined using Predictor™ hERG Fluorescence Polarization Assay (see Section 4). The modest binding of two compounds (6a and 7l) can be viewed as not significant in light of the much higher potency of the compounds (see Table 4). The cytochrome P450 inhibition profile assessed for five principal isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) demonstrated that the occasional isoform-selective inhibition is not scaffold-related. Clearly, among two compounds in each series, compounds 6c and 7c have a markedly ‘cleaner’ profile and, hence, lower likelihood of causing drug–drug interactions due to CYP inhibition (see Table 5).
Conclusions We have explored two chemical series as FFA1 receptor agonists: one (6) in which 1,3,4-thiadiazole-2-carboxamide plays the role of the core scaffold and the other (7) containing a 1,3,4-thiadiazole-2-carboxamide moiety as a periphery group ‘decorating’ the 3-phenylpropanoic g protein coupled receptors core (the latter is common for many known advanced FFA1 agonists). Both chemical series delivered compounds of sub-micromolar potency and excellent selectivity against a panel of other free fatty acid receptors (FFA2/GPR43, FFA3/GPR41 and FFA4/GPR120). The observed SAR trends have also been rationalized by in silico docking of the most active compounds onto FFA1, in comparison with the earlier described 1,3,4-thiadiazole-2-carboxamide 5 and Takeda’s discontinued clinical candidate TAK-875. The best compounds in each series have been profiled for ADME parameters (plasma and metabolic stability, plasma protein binding, LogD (pH 7.4), CYP inhibition and hERG binding). Unfortunately, the low plasma and metabolic stability observed for compounds 7 tarnishes the series from further development perspective. In contrast, series 6 displayed excellent plasma and metabolic stability, reasonable free fraction in plasma and a good CYP inhibition and hERG binding profile. Compound 6c clearly standing out in terms of the overall potency and ADME profile.
Experimental section
Acknowledgements This research was supported by the Russian Scientific Fund (project grant 14-50-00069). We are grateful to the Center for Chemical Analysis and Materials Research of Saint-Petersburg State University for providing high-resolution mass-spectrometry data.
Introduction Type 2 diabetes mellitus (T2DM), a worldwide metabolic disease, characterized by impaired glucose homeostasis due to insulin deficiency and/or desensitization [1], [2]. There are many pharmacotherapies developed for the treatment of T2DM, but most of drugs are often related to the side effects such as hypoglycemia, gastrointestinal discomfort and body weight gain [3], [4], [5], [6]. Therefore, a novel agent with improved safety and efficacy is still an unmet need for T2DM [7], [8]. The long-chain free fatty acid receptor 1 (FFA1, previously known as GPR40), a new antidiabetic target in pancreatic β-cells, enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia [9], [10], [11], [12]. Hence, the FFA1 agonists might provide enormous advantage for the treatment of T2DM by decreasing the risk of hypoglycemia.