PXL065

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PXL065
Deuteropioglitazone.svg
Clinical data
Other namesDRX-065; d-R-pioglitazone
Identifiers
  • (5R)-5-Deuterio-5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
CAS Number
PubChem CID
UNII
Chemical and physical data
Formula C19H20N2O3S
Molar mass 356.44 g·mol−1
3D model (JSmol)
  • [2H] [C@]1(C(=O)NC(=O)S1)CC2=CC=C(C=C2)OCCC3=NC=C(C=C3)CC
  • InChI=1S/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23)/t17-/m1/s1/i17D
  • Key:HYAFETHFCAUJAY-VHLRUQIKSA-N

PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH). [a] It is the deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonist activity and the associated side effects of weight gain and edema. [1] PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH [1] and X-linked adrenoleukodystrophy (X-ALD). [2] In 2022, it successfully completed a 9 month Phase 2 trial in biopsy-proven NASH patients where it met the primary endpoint for reduction in liver fat without weight gain or edema. [3] [4] [5]

PXL065 was discovered and advanced to Phase 1 by DeuteRx, LLC using the strategy of deuterium-enabled chiral switching (DECS). [6] In August 2018, PXL065 and a portfolio of deuterated thiazolidinediones (TZDs) was acquired by Poxel SA. [7]

Notes

  1. About the chemical formula: One of the hydrogens is deuterium, so a more precise formula is C19H192HN2O3S (IUPAC recommends that the chemical symbol for deuterium should be 2H, rather than D).

Related Research Articles

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<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

S<sub>N</sub>2 reaction Organic chemistry reaction

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<span class="mw-page-title-main">Cerebral edema</span> Excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

In organic chemistry, a carbanion is an anion in which carbon is negatively charged.

<span class="mw-page-title-main">Thiazolidinedione</span> Class of chemical compounds

The thiazolidinediones, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s. As of 2024, there are two FDA-approved drugs in this class, pioglitazone and rosiglitazone.

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

Rosiglitazone is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.

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

Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Hydrogen–deuterium exchange is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom, or vice versa. It can be applied most easily to exchangeable protons and deuterons, where such a transformation occurs in the presence of a suitable deuterium source, without any catalyst. The use of acid, base or metal catalysts, coupled with conditions of increased temperature and pressure, can facilitate the exchange of non-exchangeable hydrogen atoms, so long as the substrate is robust to the conditions and reagents employed. This often results in perdeuteration: hydrogen-deuterium exchange of all non-exchangeable hydrogen atoms in a molecule.

<span class="mw-page-title-main">Metabolic dysfunction–associated steatotic liver disease</span> Excessive fat buildup in the liver with other metabolic disease

Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a type of chronic liver disease. This condition is diagnosed when there is excessive fat build-up in the liver, and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease is used, and differentiated from alcohol-related liver disease (ALD) where alcohol is the predominant cause of the steatotic liver disease. The terms non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis have been used to describe different severities, the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress to it, but this progression may eventually lead to complications, such as cirrhosis, liver cancer, liver failure, and cardiovascular disease.

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

Muraglitazar is a dual peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ.

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

Remogliflozin etabonate (INN/USAN) 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. 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. Remogliflozin was commercially launched first in India by Glenmark in May 2019.

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

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<span class="mw-page-title-main">Deuterated drug</span>

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

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References

  1. 1 2 Jacques, Vincent; Bolze, Sébastien; Hallakou-Bozec, Sophie; Czarnik, Anthony W.; Divakaruni, Ajit S.; Fouqueray, Pascale; Murphy, Anne N.; Van der Ploeg, Lex H.T.; DeWitt, Sheila (2021-04-10). "Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity". Hepatology Communications. 5 (8): 1412–1425. doi:10.1002/hep4.1723. ISSN   2471-254X. PMC   8369945 . PMID   34430785.
  2. Monternier, Pierre-Axel; Singh, Jaspreet; Parasar, Parveen; Theurey, Pierre; Dewitt, Sheila; Jacques, Vincent; Klett, Eric; Kaur, Navtej; Nagaraja, Tavarekere N.; Moller, David E.; Hallakou-Bozec, Sophie (2022). "Therapeutic potential of deuterium-stabilized ('R')-pioglitazone - PXL065 for X-linked adrenoleukodystrophy". Journal of Inherited Metabolic Disease. 45 (4): 832–847. doi:10.1002/jimd.12510. PMC   9545763 . PMID   35510808.
  3. Harrison, Stephen A.; Thang, Carole; Bolze, Sébastien; DeWitt, Sheila; Hallakou-Bozec, Sophie; Dubourg, Julie; Bedossa, Pierre; Cusi, Kenneth; Ratziu, Vlad; Grouin, Jean-Marie; Moller, David E.; Fouqueray, Pascale (2023). "Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)". Journal of Hepatology. 78 (5): 914–925. doi:10.1016/j.jhep.2023.02.004. PMID   36804402. S2CID   257034807.
  4. "Poxel Announces Positive Results from Phase 2 NASH Trial (DESTINY-1) for PXL065, A Novel, Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone". Poxel SA. 2022-08-30. Retrieved 2024-03-02.
  5. Fyfe, Ian (2023). "Safer pioglitazone alternative is effective". Nature Reviews Gastroenterology & Hepatology. 20 (4): 201. doi:10.1038/s41575-023-00764-5. ISSN   1759-5053. PMID   36882559.
  6. DeWitt, Sheila; Czarnik, Anthony W.; Jacques, Vincent (2020-10-08). "Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates". ACS Medicinal Chemistry Letters. 11 (10): 1789–1792. doi:10.1021/acsmedchemlett.0c00052. ISSN   1948-5875. PMC   7549104 . PMID   33062153.
  7. "Poxel Expands Metabolic Pipeline Through Strategic Acquisition Agreement with DeuteRx for DRX-065, a Novel Clinical Stage Drug Candidate for NASH, and Other Programs". Poxel SA. 2018-08-30. Retrieved 2024-03-02.