Synthesis and Pharmacological Properties of Silicon-Containing GPR81 and GPR109A Agonists

The GPR81 and GPR109A receptors mediate antilipolytic effects and are potential drug targets for the treatment of metabolic disorders such as dyslipidemia and type 2 diabetes. There is still a need to identify potent GPR81 agonists as pharmacological tools. A high-throughput screen identified an acylurea-based GPR81 agonist lead series, with activities at the GPR109A receptor as well. To expand the chemical scope and to explore the pharmacological and pharmacokinetic consequences, a series of structurally related organosilicon compounds with a 6-sila-4,5,6,7-tetrahydrobenzo[d]thiazole skeleton was synthesized and studied for their physicochemical properties [octanol/water distribution coefficient (pH 7.4), solubility in HBSS buffer (pH 7.4)], agonistic potency at rat GPR81 and GPR109A receptors, and intrinsic clearance in human liver microsomes and rat hepatocytes. The straightforward synthesis of these organosilicon compounds offered a valuable expansion of the chemical scope in the above-mentioned GPR81 agonist lead series, provided potency and efficacy SAR, and yielded compounds with sub-micromolar GPR81 potency. This work supports the value of including silicon chemistry into the toolbox of medicinal chemistry.