Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes
| Autor: | Dann L. Parker, Randal M. Bugianesi, Birgit T. Priest, Feroze Ujjainwalla, Edward C. Sherer, Stanley Mitelman, Sharon Tong, Matthew Lombardo, William K. Hagmann, Ravi P. Nargund, Melissa Costa, Christopher Joseph Sinz, Anka G. Ehrhardt, Scott D. Edmondson, Ravi Kurukulasuriya, Xiaofang Li, Karen H. Dingley, Kate Bender, Kevin S. Ratliff, Jonathan E. Wilson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry Diabetes Mellitus Experimental Receptors G-Protein-Coupled Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Pharmacokinetics In vivo Diabetes mellitus Drug Discovery medicine Animals Oral glucose tolerance Molecular Biology Mice Knockout Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Glucose Tolerance Test Triazoles medicine.disease Rats Oxazepines 030104 developmental biology Molecular Medicine Oxazepine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:2947-2951 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.04.018 |
| Popis: | A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142. |
| Databáze: | OpenAIRE |
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