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 24^th 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:

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)

Saroglitazar | Antidiabetic Drug | Dual PPAR Inhibitor | Treatment of Diabetic Dyslipidemia | Glitazar

Saroglitazar [(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid] is a novel class of anti-diabetic drug, which target both α and γ Peroxisome Proliferator Activated Receptors (PPAR) isoforms. This new class of dual PPAR agonists, termed as glitazar, which bind to both α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome [1].

Saroglitazar: Dual PPAR Inhibitor for T2DM Patients

In February 2013, Saroglitazar became the first glitazar that has been approved by any FDA for clinical use. Saroglitazar is marketed under the trade name Lipaglyn and developed by Zydus Cadila. Saroglitazar (2 and 4 mg q.d.) is currently approved in India by Drug Controller General of India (DCGI ) for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy. Lipaglyn provides the option of a once-daily oral therapy for the patients suffering from diabetic dyslipidemia.

Saroglitazar has another first attached to it. It is the first indigenously developed NCE by any Indian company; in this case Zydus Cadila.

Lipaglyn is indicated 4 mg (or 2 mg where such a need arise) oral dose once daily. 

Saroglitazar Synthesis

WO2003009841A1: Industrial Process

Identification:

1H NMR (Estimated) for Saroglitazar

Experimental: ¹H NMR: 1.14 (3H, t, J = 6.9Hz); 2.37 (3H, s); 2.48 (3H, s); 2.92-3.06 (2H, m); 3.32-3.42 (1H, m); 3.57-3.64 (1H, m); 3.9 (2H, t, J=6.36 Hz); 4.0 (1H, dd); 4.28(2H, t, J = 6.2 Hz); 5.9 (1H, d, J = 3.3 Hz); 6.08 (1H, d, J = 3.38 Hz); 6.6 (2H, d, J = 8.5Hz); 7.1(2H, d, J = 8.5Hz); 7.26 (2H, d, J = 8.4Hz); 7.3 (2H, d, J = 8.34Hz)

Sideeffects:

The results from various clinical trials do not cite any serious adverse events for Saroglitazar. A small number of incidence reported are dyspepsia, gastritis, pyrexia, pain and chest pain. Their occurrence is nearly as those reported for placebo in the study.

None of the study reports any of the sideeffects commonly associated with PPAR inhibitors such as edema, weight gain, myopathies or derangement of liver and/or kidney functions.

Saroglitazar controversy:

Zydus Cadila says that's its antidiabetic pill is free from side-effects. One expects Saroglitazar to exhibits few (if not all) of the side-effects that occur with other members of glitazar family. I agree that in Saroglitazar case these side-effects may not be life threatening as in other marketed antidiabetic drugs such as pioglitazone, etc; but a pill with no side-effect is "hard to swallow" pill.

Lancet in one of its publication has cited three antidiabetic launched in India that have a used a very "un-scientific" technique to do so. Saroglitazar is the only NCE here, the other two being Hydroxychloroquine (already used as for rheumatoid arthritis treatment) and Berberine (a herbal preparation). Lancet cites that these drugs or preparations have been launched without any extensive clinical trials. The clinical trials done are with small sample size; and/or of very short time frame. In simple words, Lancet feels that these drugs have been "pushed" down the Indian throats. Though the originator companies have strongly refuted this publication; but the question still stay ..... how can be there no AEs? Any foreign particle (including drug molecules) trigger a wide range of receptors, some have an instantaneous reaction (or visualization); other are like slow poison, waiting for a time period to strike. Lack of time-based knowledge of effects is pretty dangerous and west knows it best; as they have launched pain-killers that killed people via heart-attacks [3].

References:

1. Agrawal, R. The first approved agent in the Glitazar's Class: Saroglitazar. Curr Drug Targets 2014, 15(2), 151-155.
2. Lohray, B. B.; et. al. Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine. WO2003009841A1
3. Luthra, A.; et. al. The marketing of unproven drugs for diabetes and dyslipidaemia in India. The Lancet Diabetes and Endocrinology 2015, 3(10), 758-760.