PXL065

{{Short description|Chemical compound}}

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| image = Deuteropioglitazone.svg

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| synonyms = DRX-065; d-R-pioglitazone

| CAS_number = 1259828-75-5

| PubChem = 49835993

| UNII = RQ8IV9N7OT

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| IUPAC_name = (5R)-5-Deuterio-5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione

| StdInChI = 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

| StdInChIKey = HYAFETHFCAUJAY-VHLRUQIKSA-N

| SMILES = [2H] [C@]1(C(=O)NC(=O)S1)CC2=CC=C(C=C2)OCCC3=NC=C(C=C3)CC

| C = 19

| H = 20

| N = 2

| O = 3

| S = 1

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PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH).{{efn|About the chemical formula: One of the hydrogens is deuterium, so a more precise formula is C{{sub|19}}H{{sub|19}}{{sup|2}}HN{{sub|2}}O{{sub|3}}S (IUPAC recommends that the chemical symbol for deuterium should be {{sup|2}}H, rather than D).}} It is the deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonist activity and the associated side effects of weight gain and edema.{{Cite journal |last=Jacques |first=Vincent |last2=Bolze |first2=Sébastien |last3=Hallakou-Bozec |first3=Sophie |last4=Czarnik |first4=Anthony W. |last5=Divakaruni |first5=Ajit S. |last6=Fouqueray |first6=Pascale |last7=Murphy |first7=Anne N. |last8=Van der Ploeg |first8=Lex H.T. |last9=DeWitt |first9=Sheila |date=2021-04-10 |title=Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity |journal=Hepatology Communications |volume=5 |issue=8 |pages=1412–1425 |doi=10.1002/hep4.1723 |issn=2471-254X |pmc=8369945 |pmid=34430785}} PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH and X-linked adrenoleukodystrophy (X-ALD).{{Cite journal |last=Monternier |first=Pierre-Axel |last2=Singh |first2=Jaspreet |last3=Parasar |first3=Parveen |last4=Theurey |first4=Pierre |last5=Dewitt |first5=Sheila |last6=Jacques |first6=Vincent |last7=Klett |first7=Eric |last8=Kaur |first8=Navtej |last9=Nagaraja |first9=Tavarekere N. |last10=Moller |first10=David E. |last11=Hallakou-Bozec |first11=Sophie |date=2022 |title=Therapeutic potential of deuterium-stabilized ('R')-pioglitazone - PXL065 for X-linked adrenoleukodystrophy |journal=Journal of Inherited Metabolic Disease |volume=45 |issue=4 |pages=832–847 |doi=10.1002/jimd.12510 |pmc=9545763 |pmid=35510808}} 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.{{Cite journal |last=Harrison |first=Stephen A. |last2=Thang |first2=Carole |last3=Bolze |first3=Sébastien |last4=DeWitt |first4=Sheila |last5=Hallakou-Bozec |first5=Sophie |last6=Dubourg |first6=Julie |last7=Bedossa |first7=Pierre |last8=Cusi |first8=Kenneth |last9=Ratziu |first9=Vlad |last10=Grouin |first10=Jean-Marie |last11=Moller |first11=David E. |last12=Fouqueray |first12=Pascale |date=2023 |title=Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1) |url=https://pubmed.ncbi.nlm.nih.gov/36804402/ |journal=Journal of Hepatology |volume=78 |issue=5 |pages=914–925 |doi=10.1016/j.jhep.2023.02.004 |pmid=36804402 |s2cid=257034807}}{{Cite web |date=2022-08-30 |title=Poxel Announces Positive Results from Phase 2 NASH Trial (DESTINY-1) for PXL065, A Novel, Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone |url=https://www.poxelpharma.com/en_us/news-media/press-releases/detail/221/poxel-announces-positive-results-from-phase-2-nash-trial |access-date=2024-03-02 |website=Poxel SA |language=en-US}}{{Cite journal |last=Fyfe |first=Ian |date=2023 |title=Safer pioglitazone alternative is effective |url=https://www.nature.com/articles/s41575-023-00764-5 |journal=Nature Reviews Gastroenterology & Hepatology |volume=20 |issue=4 |pages=201 |doi=10.1038/s41575-023-00764-5 |issn=1759-5053 |pmid=36882559|url-access=subscription }}

PXL065 was discovered and advanced to Phase 1 by DeuteRx, LLC using the strategy of deuterium-enabled chiral switching (DECS).{{Cite journal |last=DeWitt |first=Sheila |last2=Czarnik |first2=Anthony W. |last3=Jacques |first3=Vincent |date=2020-10-08 |title=Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates |journal=ACS Medicinal Chemistry Letters |language=en |volume=11 |issue=10 |pages=1789–1792 |doi=10.1021/acsmedchemlett.0c00052 |issn=1948-5875 |pmc=7549104 |pmid=33062153}} In August 2018, PXL065 and a portfolio of deuterated thiazolidinediones (TZDs) was acquired by Poxel SA.{{Cite web |date=2018-08-30 |title=Poxel Expands Metabolic Pipeline Through Strategic Acquisition Agreement with DeuteRx for DRX-065, a Novel Clinical Stage Drug Candidate for NASH, and Other Programs |url=https://www.poxelpharma.com/en_us/investors/news-events/press-releases/detail/99/poxel-expands-metabolic-pipeline-through-strategic |access-date=2024-03-02 |website=Poxel SA |language=en-US}}