Tuesday, July 12, 2016

Empagliflozin | Sodium-Glucose Co-Transporter 2 Inhibitor | SGLT2 Inhibitor I Treatment for Type 2 Diabetes Mellitus

Empagliflozin [1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yl-oxy)-benzyl]-benzene] is an oral, potent and selective inhibitor of sodium-glucose co-transporter 2 (SGLT2). Oral Empagliflozin is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus (T2DM) [1, 2].

Empagliflozin showed greater than 2500-fold selectivity for hSGLT-2 over hSGLT-1 (IC50 = 8300 nM) and more than 3500-fold selectivity over hSGLT-4 (IC50 = 11000 nM) [3].
Empagliflozin: 2D and 3D Structure

In several phase III trials (typically 24 weeks or more duration) and extension studies (typically more than 76 weeks’ treatment), Empagliflozin monotherapy or add-on therapy to other anti-hyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. As add-on therapy to metformin, Empagliflozin driven improvement in glycaemic control is noninferior to glimepiride at 52 weeks but superior to glimepiride at 104 weeks. Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. 

Empagliflozin was approved in Europe in May 2014 and was approved by the FDA in August 2014 as once-daily oral tablet for adults with type 2 diabetes.

Empagliflozin Synthesis

Org Lett 2014, 16(16), 4090-4093: An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin from 5-iodo-2-chlorobenzoic acid is described. The key tactical stage involves I/Mg exchange of aryl iodide followed by addition to glucono lactone in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH2Cl2/MeCN to afford Empagliflozin in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch. Also see Ref. 5.


1H NMR (Estimated) for Empagliflozin

Experimental: 1H NMR (400 MHz, DMSO-d6) 7.70 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 2.0, 8.4 Hz, 1H), 7.17 (ABq, J = 8.8 Hz, 2H), 6.82 (ABq, J = 8.8 Hz, 1H), 4.95 (m, 3H), 4.84 (d, J = 6.4 Hz, 1H), 4.46 (t, J = 6.0 Hz, 1H), 3.98 (m, 3H), 3.87-3.67 (m, 5H), 3.46-3.42 (m, 1H), 3.27-3.10 (m, 4H), 2.23-2.14 (m, 1H), 1.96-1.89 (m, 1H).

13C NMR (Estimated) for Empagliflozin

Experimental: 13C NMR (400 MHz, DMSO-d6) δ 155.4, 139.6, 137.7, 131.9, 131.5, 130.9, 129.6, 128.6, 127.4, 115.1, 81.2, 80.6, 78.2, 76.9, 74.7, 72.2, 70.3, 66.4, 61.3, 37.5, 32.4.

1. McGill, J. B. The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review. Diabetes Ther 2014, 5(1), 43-63. (free article)
2. Scott, L. J. Empagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus. Drugs 2014, 74, 1769-1784. (FMO only)
3. Grempler, R.; et. al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012, 14(1), 83-90. (FMO only) (an excellent work published.)
4. Wang, X. J.; et. al. Efficient synthesis of Empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a ß-glycopyranoside. Org Lett 2014, 16(16), 4090-4093. (FMO only)
5. Himmelsbach, F.; et. al. Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof. WO2005092877A1