Sunday, June 26, 2016

Luseogliflozin I Sodium Glucose Co-transporter 2 Inhibitor I Treatment for Diabetes Mellitus

Luseogliflozin [(2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}- 6-(hydroxymethyl)thiane-3,4,5-triol hydrate] is an oral, 1-thio-D-glucitol derivative Sodium glucose co-transporter 2 (SGLT2) inhibitor that is developed for the treatment of type 2 diabetes mellitus (T2DM).

Luseogliflozin is a potent and selective SGLT2 inhibitor, with a 50% inhibitory concentration (IC50) of 2.26 nM, which is 1765 times lower than its IC50 for SGLT1 (IC50 = 3990 nM). This potency allows the administration of lower doses of Luseogliflozin compared with other SGLT2 inhibitors for the treatment of T2DM.

Luseogliflozin: 2D and 3D Structure

Luseogliflozin an orally active second-generation SGLT2 inhibitor is developed for the treatment of patients with type 2 diabetes mellitus (T2DM). In March 2014, the drug received its first global approval for this indication in Japan, either as monotherapy or in combination with other antihyperglycaemic agents.

Diabetes and SGLT Inhibitors
Good control of blood glucose can be achieved by a controlled diet and physical exercise. Diabetes is associated with an increased risk of both macrovascular (cardiovascular disease) and microvascular (nephropathy, retinopathy, and neuropathy) complications. Diabetes can also be managed by orally active drugs including sulfonylurea, biganide etcs.
Sodium-dependent glucose transporters (SGLTs) present on the chronic membrane of the intestine and kidney play an important role in the absorption and reabsorption of glucose. Inhibition of renal glucose reabsorption is emerging as a novel therapy for patients with type 2 diabetes mellitus (T2DM).
In particular, blocking the sodium-glucose cotransporter 2 (SGLT2)-a low-affinity high-capacity transporter localised to the renal proximal tubules-has been shown to suppress glucose reabsorption, leading to increased urinary excretion with a concomitant reduction in plasma glucose levels. Compounds selective for SGLT2 are desirable as SGLT1 is highly expressed in the gastrointestinal tract but only moderately expressed in the kidneys.
SGLT2 inhibitors have an insulin-independent mechanism of action; these drugs are expected to improve glycemic control with a low risk of major hypoglycemic events. Furthermore, total calorie loss through urinary glucose excretion may not cause weight gain and may even achieve weight loss.

Dosages and Approvals:
Luseogliflozin [Tradename: Lusefi] is a selective SGLT2 inhibitor, which received its first marketing approval in Japan for the treatment of T2DM on the 24th of March 2014. The drug has received approval as 2.5 and 5 mg oral tablets with a recommended starting dose of 2.5 mg once daily. This may be increased to 5 mg once daily if necessary for optimal clinical effect.
Luseogliflozin is manufactured by Taisho Pharmaceutical, Japan and co-marketed by both Taisho and Novartis in Japan. Novartis licensed the marketing rights for Luseogliflozin in Japan. Under the terms of this agreement, Taisho will receive an upfront payment and milestone payments from Novartis.

Luseogliflozin Synthesis

J Med Chem 2010, 53(8), 3247-3261:

Final Synthesis:


1H NMR (Estimated) for Luseogliflozin

1. Markham, A.; et. al. Luseogliflozin: first global approval. Drugs 2014, 74(8), 945-50. (FMO only)
2. Seino, Y. Luseogliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother 2014, 15(18), 2741-9. (FMO only)
3. Yamamoto, K.; et. al. TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br J Pharmacol 2011, 164(1), 181-91. (Free copy)
4. Kakinuma, H.; et. al. (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment. J Med Chem 2010, 53(8), 3247-3261. (FMO only)