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  • The highest metabolic stability observed for compound

    2022-05-12

    The highest metabolic stability observed for compound 4k (EC50=0.41μM corresponding to 218ng/mL) among the four selected frontrunner candidates was the principal decisive point in nominating this compounds for pharmacokinetic characterization in mice at the dosage of 10mg/kg (administered intravenously and orally). As can be seen from pharmacokinetic parameters presented in Table 4, compound 4k demonstrated satisfactory oral bioavailability (F, %) and plasma levels commensurate with or significantly higher than the in vitro EC50 value, on oral and intravenous administration, respectively.
    Conclusions The toxicity associated with high lipophilicity of previous FFA1 agonists has been a limiting factor in the progression through clinical trials. Here, we have reported on a novel series of FFA1 (GPR40) agonists. The series was designed based on the basic amine spirocyclic periphery motif present in Eli Lilly’s advance FFA1 agonist LU2881835. A diverse set of 19 compounds was synthesized via decoration of the 3-[4-(benzyloxy)phenyl]propanoic Levofloxacin core building block with a set of spirocyclic piperidines synthesized from Boc-protected 1-oxa-9-azaspiro[5.5]undecan-4-ol which, in turn, had been reported as amenable on multigram scale via Prins chemistry. The compounds displayed meaningful structure–activity relationships in vitro stimulating calcium flux in FFA1-overexpressing CHO cells and four frontrunner compounds having EC50 values in the 0.055–0.41μM range have been identified. The compounds displayed an overall satisfactory profile except for low metabolic stability. Compound 4k having the highest mouse liver microsome stability and EC50=0.41μM was evaluated for pharmacokinetics in mice on intravenous and oral administration. This lead compound demonstrated high plasma levels achieved even on oral administration of 10mg/kg dose and absolute oral bioavailability (F) of Levofloxacin 10.3%. This compound represents a promising lead for further optimization and development of the novel class of therapies against type 2 diabetes mellitus.
    Experimental section
    Acknowledgements
    Introduction Agonists of free fatty acid receptor 1 (FFA1, known as GPR40 prior to its de-orphaning in 2003) hold a particular promise to become an attractive alternative to the currently used anti-diabetic agents, most of which lower glucose levels irrespective of the basal blood glucose concentration and can cause hypoglycemia. Under normal glycemia, FFA1 expression (primarily, in pancreatic islets of Langerhans) is low and increases only in hyperglycemic state. At higher expression levels, activation of the receptor by small molecule agonists triggers a signaling cascade that raises the levels of insulin, lowers the glucose levels and, consequently, downregulates FFA1 itself. Thus, the new therapeutic approach does not carry the danger of causing hypoglycemia (i.e., bringing the blood glucose concentration to dangerously low levels). This has led to an extensive research effort aimed at developing a new class of agents to treat type 2 diabetes mellitus (T2DM). The area of FFA1agonist-based therapy was adversely affected by the late-2013 discontinuation of phase III trial of Takeda’s first-in-class agent fasiglifam (TAK-875). At the time of writing this manuscript, merely one clinical trial of an FFA1 agonist (Piramal’s compound P11187 of undisclosed structure) was underway. The unexpected toxicity issues aside, the antidiabetic efficacy of TAK-875 was established in the course of Takeda’s clinical investigation of the drug, thereby providing the proof-of-principle for the entirely new therapeutic approach. Therefore, the future quest for efficacious and safe FFA1 agonists should primarily focus on tackling their liver toxicity profile. The toxicity has been linked to the high lipophilicity of TAK-875 as well as most reported FFA1 agonists. Increasing the total polar surface area of FFA1 agonists could, in principle, provide a straightforward solution to the problem. However, TAK-875 and many other advanced compounds of this class (such as Amgen’s AMG-837, and Eli Lilly’s LY2881835) are based on the 3-[4-(benzyloxy)phenyl]propanoic acid core, which mimics the fatty acid endogenous ligands of the receptor (Fig. 1). Hence, imparting too much polarity to a FFA1 agonist may simply render the ligand inactive.