Ipragliflozin Chemical Properties

Melting point:

155-157°C

Boiling point:

628.8±55.0 °C(Predicted)

Density 

1.452

storage temp. 

Refrigerator

solubility 

DMSO (Slightly), Methanol (Slightly)

pka

13.27±0.70(Predicted)

form 

Solid

color 

White to Off-White

InChI

InChI=1/C21H21FO5S/c22-15-6-5-12(21-20(26)19(25)18(24)16(10-23)27-21)7-13(15)9-14-8-11-3-1-2-4-17(11)28-14/h1-8,16,18-21,23-26H,9-10H2/t16-,18-,19+,20-,21+/s3

InChIKey

AHFWIQIYAXSLBA-OPUVIHLBNA-N

SMILES

O1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1C1C=CC(F)=C(CC2=CC3C=CC=CC=3S2)C=1 |&1:1,4,6,8,10,r|

Ipragliflozin Usage And Synthesis

Description

Ipragliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor (IC₅₀ = 7.4 nM in CHO cells expressing the human cotransporter). It is selective for SGLT2 over SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6 (IC₅₀s = 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.

Trade name

Suglat

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

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