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

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.

Pd-Catalyzed Carbonylation of Acyl Azides

“…Acyl urea derivatives are common motifs in pharmaceuticals and agrochemicals . The traditional method for accessing acyl urea is the transformation of amides with phenyl carbamates, which produces stoichiometric phenol as a byproduct . Other approaches involve the coupling of isocyanates with amides and acyl isocyanates with amines, both of which usually require the use of unfriendly phosgene .…”

Hydroaminoalkylation of Allylsilanes and a One‐Pot Procedure for the Synthesis of 1,5‐Benzoazasilepines

“…Although one method for the development of new drugs is the high‐throughput synthesis and high‐throughput screening approach, an alternative possibility is the sila‐substitution (Si/C exchange) in known drug scaffolds . The feasibility of the latter approach, which was pioneered by the Tacke group,–– has strongly been underlined by a large number of examples in which sila‐substitution significantly affects the features of a drug. For example, the different geometry and bond lengths of Si−C (187 pm) and C−C bonds (154 pm) as well as the different p K a values of silanols (p K a(DMSO) of Ph 3 SiOH=16.6) compared to alcohols (p K a(DMSO) of Ph 3 COH=17.0) are important aspects which may favor sila‐substituted drugs over the corresponding carbon species .…”

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

“…129 Recently, the Tacke group reported the synthesis of several silicon incorporated 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives of lead compound 140 (Figure 35). 130 They evaluated the in vitro biological activity using GPR81 and GPR109A, two novel and potential targets for the treatment of diabetes. Although silicon incorporation reduced potency against GPR81, it slightly improved the potency with GPR109A.…”