| Title: | Dihydropyrazole GPR40 Modulators | ||
| Patent Application Number: | WO 2014/078608 Al | Publication Date: | 22 May 2014 |
| Priority Application: | US 61/727,191 | Priority Date: | 16 November 2012 |
| Inventors: | Hernandez, A. S.; Ellsworth, B. A.; Ewing, W. R.; Chen, B. | ||
| Assignee Company: | Bristol-Myers Squibb Company, P.O. Box 4000, Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, USA | ||
| Disease Area: | Diabetes and related conditions | Biological Target: | GPR40 G protein-coupled receptor |
| Summary: | The invention in this patent application relates to novel carboxy dihydropyrazole derivatives represented generally by formula (I). These compounds are modulators of GPR40 (a G-protein coupled receptor) and may potentially be useful for the treatment or prophylaxis of diabetes and related conditions. | ||
| The type 2 diabetes is the most common form of diabetes mellitus. It is characterized by increasing insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. β-cells are located in the islets of Langerhans of the pancreas and primarily function to store and release insulin. Plasma free fatty acids (FFAs) are implicated in mediation of insulin resistance. They are believed to influence insulin secretion from β-cells mainly by enhancing glucose-stimulated insulin secretion (GSIS). | |||
| The G-protein coupled receptors (GPCRs) expressed in the β-cells are known to modulate the release of insulin in response to changes in plasma glucose levels. One of the G-protein coupled receptors is GPR40, also known as fatty acid receptor 1 (FFAR1). It is a membrane-bound FFA receptor, which is expressed in the pancreatic islets, specifically in β-cells, and mediates medium to long chain fatty acid induced insulin secretion. GPR40 is also expressed in enteroendocrine cells wherein activation promotes the secretion of gut incretin hormones, such as GLP-1, GIP, CCK, and PYY. These hormones stimulate insulin secretion in response to meals. | |||
| GPR40 modulators such as the compounds described in this patent application may potentially provide a treatment for type 2 diabetes and enhanced glycemic control through exerting an incretin effect to promote GSIS. It may also be potentially effective when used in combination with a broad range of antidiabetic drugs. | |||
| Important Compound Classes: |  |
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| Key Structures: | The inventors described the synthesis of 78 examples of formula (I) compounds. Many of the compounds were resolved into pure enantiomers. The following compounds are representative of the disclosed compounds in which both enantiomers were isolated and labeled as isomers 1 and 2:
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| Biological Assay: |
In Vitro GPR40 Assays:
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| Biological Data: | The disclosed examples were tested in the human GRP40 in vitro assay and found having hGRP40 modulating activity reported ashGPR40 EC50. The following Table contains the EC50 data for the above examples:
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| Claims: | Claims 1–10: Composition of matter, variations of formula (I) | ||
| Claims 11–13: Pharmaceutical composition | |||
| Claims 14–15: Use of compounds | |||
| Recent Review Articles: | Poitout V.; Lin D. C.-H.. Drug Discovery Today 2013, 18(23–24), 1301–1308. | ||
| Basu A.; Kudva Y. C.; Basu R.. Diabetes Care 2013, 36(2), 185–187. | |||
| Vangaveti V.; Shashidhar V.; Jarrod G.; Baune B. T.; Kennedy R. L.. Ther. Adv. Endocrinol. Metab. 2010, 1(4), 165–175. | |||
| Medina J. C.; Houze J. B.. Annu. Rep. Med. Chem. 2008, 43, 75–85. | |||
The authors declare no competing financial interest.