Description
Ipragliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor (IC
50 = 7.4 nM in CHO cells expressing the human cotransporter). It is selective for SGLT2 over SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6 (IC
50s = 1.9, 30.4, 15.9, 0.46, and 10.4 μM, respectively). Ipragliflozin (0.1-3 mg/kg) decreases plasma levels of insulin and glucose in an oral glucose tolerance test in a mouse model of diabetes induced by high-fat diet, streptozotocin (STZ; ), and nicotinamide . It decreases plasma and hepatic IL-6, TNF-α, chemokine (C-C motif) ligand 2 (CCL2), and C-reactive protein (CRP) levels in the same model when administered at a dose of 3 mg/kg per day for 28 days.
History
Ipragliflozin L-proline was approved in Japan in January 2014 for the treatment of type 2 diabetes. The drug was discovered by Astellas Pharma and co-developed and marketed with Kotobuki Pharmaceutical and Merck Sharp Dohme as Suglat. Similar to empagliflozin (XIII), ipragliflozin L-proline is a sodium-glucose 1956 A. C. Flick et al. / Bioorg. Med. Chem. 24 (2016) 1937–1980 co-transporter-2 inhibitor which prevents glucose reabsorption by excreting excess glucose in the urine. Ipragliflozin exhibits remarkable selectivity over SLGT-1 (>250x).
Uses
Ipragliflozin is a potent and selective inhibitor of sodium-glucose cotransporter-2 (SGLT2) and can serve as a potential agent for the treatment of type 1 and type 2 diabetes.
Definition
ChEBI: Ipragliflozin is a glycoside.
Synthesis
Commercial 5-bromo-2-fluorobenzaldehyde (123) was
subjected to nucleophilic attack upon subjection to lithiated
benzo[b]thiophene (124) to afford the dibenzylic alcohol 125 in
85% yield. This alcohol was then halogenated by means of thionyl
chloride in acetonitrile to give 126, which was followed by treatment
with sodium borohydride to give rise to 2-(5-bromo-2-fluorophenyl)-
1-benzothiophene (127), which was isolated by
crystallization from 2-propanol and methanol in 81% yield across
the two steps. Bromide 127 then underwent lithium¨Chalogen
exchange prior to exposure to 2,3,4,6-tetrakis-O-(trimethylsilyl)-
D-glucono-1,5-lactone (128) in toluene. Without workup, the
resulting mixture was treated with a solution of methanol and
HCl at 0 C to give a globally desilylated a-glucopyranoside intermediate.
Subjection to acetic anhydride and 4-dimethylaminopyridine
furnished tetra-O-acetyl ipragliflozin (129) in 75% yield for
the 3 steps. Polyacetate 129 was then saponified using aqueous
sodium hydroxide and the product was crystallized from methanol
and water and subsequently treated with D-proline in ethanol to
furnish the desired product ipragliflozin D-proline (XVI) in 68%
yield.
Mode of action
Ipragliflozin is a selective SGLT2 (sodium-glucose co-transporter 2) inhibitor discovered through research collaboration with Kotobuki Pharmaceutical Co., Ltd. SGLTs are membrane proteins that exist on the cell surface and transfer glucose into cells. SGLT2 is a subtype of the sodium-glucose co-transporters and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys. Ipragliflozin reduces blood glucose levels by inhibiting the reuptake of glucose.
References
[1] Patent: EP2105442, 2009, A1. Location in patent: Page/Page column 13
[2] Patent: CN108276396, 2018, A. Location in patent: Paragraph 0041; 0052; 0053; 0068; 0083
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 10, p. 3263 - 3279
[4] Patent: EP2009010, 2008, A1. Location in patent: Page/Page column 6-7
