Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Treatment of Diabetes, Obesity, Dyslipidemia, and Related Disorders with GPR119 Agonists
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Ahmed F. Abdel-Magid* Therachem Research Medilab, LLC., 100 Jade Park, Chelsea, Alabama 35043, United States disorders, high blood pressure, chronic low grade inflammation, Important Compound Classes. retinopathy, neuropathy, nephropathy, atherosclerosis, coronary heart disease, endothelial dysfunction, and bone-related diseases such as osteoporosis, rheumatoid arthritis, or osteoarthritis. While there are many known GPR119 agonists in the art, there is still a need for the invention of novel active GPR119 agonists, such as the compounds of this patent application, which can be used therapeutically for the prevention and/or Title. Azetidine Compounds as GPR119 Modulators for the treatment of diabetes, obesity, dyslipidemia, or related disorders. Treatment of Diabetes, Obesity, Dyslipidemia, and Related Key Structures. The inventors disclosed the structures and Disorders synthesis details of 102 compounds of formula I (in five strucPatent Application Number. WO 2018/153849 A1 turally related categories). The following compounds are reprePublication Date. 30 August 2018 sentative examples: Priority Application. EP 17305189.7 Priority Date. 21 February 2017 Inventors. Schwink, L.; Buning, C.; Glombik, H.; Poverlein, C.; Ritter, K.; Halland, N.; Lohmann, M. Assignee Company. Sanofi; 54 rue La Boètie, 75008 Paris, France Disease Area. Diabetes, obesity, dyslipidemia, and related disorders. Biological Target. G protein-coupled receptor 119 (GPR119) Summary. The invention in this patent application relates to azetidine-containing compounds represented generally by formula I. These compounds are GPR119 modulators and may be useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia, and related disorders. G protein-coupled receptor 119 (GPR119) is expressed predominantly in the pancreas and in the K- and L-cells of the intestine. It is believed that modulation of GPR 119 may be beneficial in treatment of diabetes and related disorders by augmenting the secretion of insulin and intestinal hormones like the gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). This belief is based on several in vitro studies of which show that GPR 119 agonists can activate the cAMP pathway in the gut and in the pancreas derived cell lines to mediate the secretion of GLP-1 and insulin, respectively. The augmented secretion of insulin was found to be strictly glucose-dependent, which can be beneficial because it minimizes the undesired induction of hypoglycemic episodes. Activation of GPR119 may also improve the function and mass of beta cells. Thus, GPR-119 agonists may provide additional benefits such as reduced food intake as a result of the release of intestinal peptides. Studies in rodents also showed that GPR 119 agonists cause glucose lowering effects, accompanied by decreased food intake and weight loss. Recent human clinical trials with GPR119 agonists added evidence for positive impacts on lipid parameters such as elevation of HDL-C together with lowering of LDL-C and triglycerides. Studies have shown that modulators of GPR119, particularly agonists, can potentially be used in the prevention and/or treatment of metabolic disorders. Examples of such metabolic disorders and diseases include type 2 diabetes mellitus, type 1 diabetes mellitus, impaired glucose tolerance, insulin resistance, loss of beta cell function, hyperglycemia, hypercholesterolemia, dyslipidemia, hypertriglyceridemia, syndrome X, metabolic synReceived: December 9, 2018 drome, obesity, fatty liver, steatosis, steatohepatitis, nonalcoholic steatohepatitis (NASH), cirrhosis, micro- and macro-vascular © XXXX American Chemical Society
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DOI: 10.1021/acsmedchemlett.8b00622 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Assay. • Functional Cellular Assays Measuring GPR119-mediated cAMP Release Biological Data. The biological data obtained from testing the above representative examples are listed in the following table:
Recent Review Articles. 1. Ritter, K.; Buning, C.; Halland, N.; Poeverlein, C.; Schwink, L. J. Med. Chem. 2016, 59 (8), 3579−3592. 2. Scheen, A. J. Expert Opin. Investig. Drugs 2016, 25 (4), 405−422. 3. Kang, S.-U. Drug Discovery Today 2013, 18 (23−24), 1309−1315.
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[email protected]. Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.8b00622 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
