title: 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.
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Baus
authors.affiliation: AstraZeneca R&D Mölndal, CVMD Innovative Medicines, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.affiliation: AstraZeneca R&D Mölndal, CVMD Innovative Medicines, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Wellner
authors.affiliation: AstraZeneca R&D Mölndal, CVMD Innovative Medicines, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Gustafsson
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074, Würzburg, Germany. r.tacke@uni-wuerzburg.de.
authors.forename: Reinhold
authors.identifier: http://orcid.org/0000-0003-4532-2647
authors.initials: R
authors.lastname: Tacke
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D017646:Organosilicon Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; C000603107:GPR81 protein, rat; C554445:Hcar2 protein, rat; D017646:Organosilicon Compounds; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C005465:benzothiazole
keywords: GPR109A receptor; GPR81 receptor; silicon; silicon-based drugs; structure-activity relationships