Remogliflozin etabonate

Last updated
Remogliflozin etabonate
Remogliflozin etabonate structure.svg
Clinical data
Routes of
administration 		By mouth
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Metabolism Remoglifozin is metabolized primarily by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19 to GSK 279782 (the active metabolite) and GSK 333081 before being glucuronidated to generate inactive glucuronide conjugates. [1]
Identifiers
  • 5-Methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside
CAS Number
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H38N2O9
Molar mass 522.595 g·mol−1
3D model (JSmol)
  • OC1C(COC(=O)OCC)OC(C(O)C1O)Oc(nn(C(C)C)c2C)c2Cc3ccc(cc3)OC(C)C
  • InChI=1S/C26H38N2O9/c1-7-33-26(32)34-13-20-21(29)22(30)23(31)25(36-20)37-24-19(16(6)28(27-24)14(2)3)12-17-8-10-18(11-9-17)35-15(4)5/h8-11,14-15,20-23,25,29-31H,7,12-13H2,1-6H3/t20-,21-,22+,23-,25+/m1/s1 X mark.svgN
  • Key:UAOCLDQAQNNEAX-ABMICEGHSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Remogliflozin etabonate (INN/USAN) [2] is a drug of the gliflozin class for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes. Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being developed by BHV Pharma, a wholly owned subsidiary of North Carolina, US-based Avolynt, and Glenmark Pharmaceuticals through a collaboration with BHV. [3] In 2002, GlaxoSmithKline (GSK) received a license to use it. From 2002 to 2009, GSK carried out a significant clinical development program for the treatment of type-2 diabetes mellitus in various nations across the world and obesity in the UK. Remogliflozin etabonate's pharmacokinetics, pharmacodynamics, and clinical dose regimens were characterized in 18 Phase I and 2 Phase II investigations. Due to financial concerns, GSK stopped working on remogliflozin and sergliflozin, two further SGLT2 inhibitors that were licensed to the company, in 2009. [4] Remogliflozin was commercially launched first in India by Glenmark in May 2019.

Contents

Clinical trials

Remogliflozin etabonate was shown to enhance urinary glucose excretion in rodents and humans. Early studies in diabetics improved plasma glucose levels. [5] [6] Remogliflozin etabonate has been studied at doses up to 1000 mg. [7] A pair of 12-week phase 2b randomized clinical trials of diabetics published in 2015, found reductions in glycated hemoglobin and that it was generally well tolerated. [8] In a meta-analysis published by Dutta et al. involving data from 3 randomized controlled trials (535 patients), remogliflozin was noted to have similar glycaemic efficacy (reduction in HbA1c and fasting glucose) as compared to dapagliflozin and pioglitazone. [9] A study concluded that concomitant administration of remogliflozin etabonate, either 500 mg or 750 mg BID (twice a day), with metformin 2000 mg BID was safe and effective in patients with type 2 diabetes mellitus during the observation period. [10]

Method of action

Remogliflozin etabonate is a pro-drug of remogliflozin. Remogliflozin inhibits the sodium-glucose transport proteins (SGLT), which are responsible for glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine. [11] Remogliflozin is selective for SGLT2.

See also

Related Research Articles

<span class="mw-page-title-main">Diabetic ketoacidosis</span> Medical condition

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of consciousness. A person's breath may develop a specific "fruity" smell. The onset of symptoms is usually rapid. People without a previous diagnosis of diabetes may develop DKA as the first obvious symptom.

<span class="mw-page-title-main">Type 2 diabetes</span> Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

<span class="mw-page-title-main">Metformin</span> Medication used to treat diabetes by reducing glucose levels

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.

Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Glycosuria</span> Medical condition

Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused by elevated blood glucose levels, most commonly due to untreated diabetes mellitus. Rarely, glycosuria is due to an intrinsic problem with glucose reabsorption within the kidneys, producing a condition termed renal glycosuria. Glycosuria leads to excessive water loss into the urine with resultant dehydration, a process called osmotic diuresis.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

<span class="mw-page-title-main">Renal glycosuria</span> Medical condition

Renal glycosuria is a rare condition in which the simple sugar glucose is excreted in the urine despite normal or low blood glucose levels. With normal kidney (renal) function, glucose is excreted in the urine only when there are abnormally elevated levels of glucose in the blood. However, in those with renal glycosuria, glucose is abnormally elevated in the urine due to improper functioning of the renal tubules, which are primary components of nephrons, the filtering units of the kidneys.

<span class="mw-page-title-main">Sodium/glucose cotransporter 2</span> Protein-coding gene in the species Homo sapiens

The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 gene.

<span class="mw-page-title-main">Dapagliflozin</span> Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease.

<span class="mw-page-title-main">Sergliflozin etabonate</span> Chemical compound

Sergliflozin etabonate is an investigational anti-diabetic drug being developed by GlaxoSmithKline. It did not undergo further development after phase II.

<span class="mw-page-title-main">Phlorizin</span> Chemical compound

Phlorizin is a glucoside of phloretin, a dihydrochalcone. A white solid, samples often appear yellowing to impurities. It is of sweet taste and contains four molecules of water in the crystal. Above 200 °C, it decomposes to give rufin. It is poorly soluble in ether and cold water, but soluble in ethanol and hot water. Upon prolonged exposure to aqueous solutions phlorizin hydrolyzes to phloretin and glucose.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes. It is not recommended for type 1 diabetes. It is taken by mouth.

<span class="mw-page-title-main">Tofogliflozin</span> Chemical compound

Tofogliflozin is an experimental drug for the treatment of diabetes mellitus and is being developed by Chugai Pharma in collaboration with Kowa and Sanofi. It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. Several medications of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

<span class="mw-page-title-main">Ipragliflozin</span> Chemical compound

Ipragliflozin is a pharmaceutical drug for treatment of type 2 diabetes. Ipragliflozin, jointly developed by Astellas Pharma and Kotobuki Pharmaceutical, was approved in Japan on January 17, 2014, and in Russia on May 22, 2019.

Luseogliflozin is a pharmaceutical drug used for the treatment of type 2 diabetes mellitus. It was approved for use in Japan in 2014. In a meta-analysis involving data from 10 randomized controlled trials, Dutta et. al. demonstrated the good glycaemic efficacy and safety of luseogliflozin 2.5mg/day as compared to placebo. Additional benefits include significant reduction in systolic blood pressure, serum triglycerides (-12.60mg/dl), uric acid (-0.48mg/dl) and alanine aminotransferase as compared to placebo, highlighting the beneficial impact on the different aspects of metabolic syndrome.

Bexagliflozin, sold under the brand name Brenzavvy, is an antidiabetic medication used to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise. It is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is taken by mouth.

References

  1. ↑ Markham, A.J.D., Remogliflozin etabonate: first global approval. 2019. 79(10): p. 1157-1161.
  2. ↑ Statement on a nonproprietory name adopted by the USAN council
  3. ↑ "Avolynt Announces Completion of Phase 2b BRID Study of SGLT2 Inhibitor Remogliflozin-Etabonate" (Press release). Avolynt, Inc. Retrieved July 24, 2018.
  4. ↑ Mohan, V., et al., Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. 2020: p. 2487-2501.
  5. ↑ Mudaliar S, Armstrong DA, Mavian AA, O'Connor-Semmes R, Mydlow PK, Ye J, et al. (November 2012). "Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2, improves serum glucose profiles in type 1 diabetes". Diabetes Care. 35 (11): 2198–200. doi:10.2337/dc12-0508. PMC   3476920 . PMID   23011728.
  6. ↑ Dobbins RL, O'Connor-Semmes R, Kapur A, Kapitza C, Golor G, Mikoshiba I, et al. (January 2012). "Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients". Diabetes, Obesity & Metabolism. 14 (1): 15–22. doi:10.1111/j.1463-1326.2011.01462.x. PMID   21733056. S2CID   23372554.
  7. ↑ Sykes AP, O'Connor-Semmes R, Dobbins R, Dorey DJ, Lorimer JD, Walker S, et al. (January 2015). "Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes". Diabetes, Obesity & Metabolism. 17 (1): 94–7. doi: 10.1111/dom.12391 . PMID   25223369. S2CID   6436562.
  8. ↑ Sykes AP, Kemp GL, Dobbins R, O'Connor-Semmes R, Almond SR, Wilkison WO, et al. (January 2015). "Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes". Diabetes, Obesity & Metabolism. 17 (1): 98–101. doi:10.1111/dom.12393. PMID   25238025. S2CID   25280330.
  9. ↑ Dutta D, Jindal R, Mehta D, Khandelwal D, Sharma M (Nov 2021). "Efficacy and safety of novel sodium glucose cotransporter-2 inhibitor remogliflozin in the management of type 2 diabetes mellitus: A systematic review and meta-analysis". Diabetes Metab Syndr. 15 (6): 102315. doi:10.1016/j.dsx.2021.102315. PMID   34700292. S2CID   239491862.
  10. ↑ Dobbins, R., et al., Assessment of safety and tolerability of remogliflozin etabonate (GSK189075) when administered with total daily dose of 2000 mg of metformin. 2021. 22: p. 1-11.
  11. ↑ "Molecule of the Month: Dapagliflozin". Prous Science. November 2007. Archived from the original on January 6, 2008.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.