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.
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| 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.
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:
Identifications:
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| 1H NMR (Estimated) for Luseogliflozin |
References:
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)
