Synthesis and Pharmacological Properties of Silicon‐Containing GPR81 and GPR109A Agonists. Issue 12 (13th October 2015)

• Record Type: Journal Article
• Authors: Geyer, Marcel; Baus, Johannes A.; Fjellström, Ola; Wellner, Eric; Gustafsson, Linda; Tacke, Reinhold
• Is Part Of: ChemMedChem. Volume 10:Issue 12(2015:Dec.)
• Page Start: 2063
• Page End: 2070
• Publication Date: 2015-10-13
• Subjects: GPR81 receptor -- GPR109A receptor -- silicon -- silicon-based drugs -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500343
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Quaternary silicon atoms : Compounds1 a –1 f and2 a –2 f were synthesized as part of a systematic SAR analysis within a new GPR81 agonist lead series (with activities also on the GPR109A receptor) and were 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.