Tolimidone

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Tolimidone
Clinical data
Other namesCP-26154, MLR-1023
Identifiers
  • 5-(3-methylphenoxy)pyrimidin-2(1H)-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.230.742 Edit this at Wikidata
Chemical and physical data
FormulaC11H10N2O2
Molar mass202.213 g·mol−1
3D model (JSmol)
  • O=C2/N=C\C(\Oc1cc(ccc1)C)=C/N2

Tolimidone (CP-26154; MLR-1023) is a compound which was discovered by scientists at Pfizer, was found to stimulate secretion of gastric mucosa, and was in development by Pfizer as a drug candidate to treat gastric ulcers but was abandoned.[1][2][3][4] After the patent on the compound expired, scientists at the company Melior Discovery identified it as a potential drug candidate for diabetes through a phenotypic screen.[4] The company proceeded to show that MLR-1023 is an allosteric activator of Lyn kinase with an EC50 of 63 nM.[5][6] As of 2012 Melior was repurposing it for diabetes.[1][7] In June 2016, the company reported positive results from their Phase 2a clinical study in diabetic subjects[8][9]

References

  1. ^ a b Saporito MS, Lipinski CA, Reaume AG (2012). "Chapter 9:Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates". In Barratt MJ, Frail DE (eds.). Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. John Wiley & Sons. p. 270. ISBN 978-1-118-27439-2.
  2. ^ "Tolimidone". AdisInsight. Springer Nature Switzerland AG. Retrieved 26 August 2017.
  3. ^ Lipinski CA, Stam JG, Pereira JN, Ackerman NR, Hess HJ (September 1980). "Bronchodilator and antiulcer phenoxypyrimidinones". Journal of Medicinal Chemistry. 23 (9): 1026–1031. doi:10.1021/jm00183a012. PMID 7411545. Compound 3 has been assigned the nonproprietary (USAN) name tolimidone
  4. ^ a b Lipinski CA, Reaume AG (May 2020). "High throughput in vivo phenotypic screening for drug repurposing: Discovery of MLR-1023 a novel insulin sensitizer and novel Lyn kinase activator with clinical proof of concept". Bioorganic & Medicinal Chemistry. 28 (9): 115425. doi:10.1016/j.bmc.2020.115425. PMID 32201192.
  5. ^ Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS (July 2012). "The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes". The Journal of Pharmacology and Experimental Therapeutics. 342 (1): 23–32. doi:10.1124/jpet.112.192187. PMID 22431203. S2CID 7288053.[permanent dead link]
  6. ^ Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG (July 2012). "MLR-1023 is a potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo". The Journal of Pharmacology and Experimental Therapeutics. 342 (1): 15–22. doi:10.1124/jpet.112.192096. PMID 22473614. S2CID 26419896.
  7. ^ "Melior Pharmaceuticals Announces Positive Results in Phase 2B Study with Tolimidone for Type 2 Diabetes" (Press release). 14 May 2019.
  8. ^ "Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study". www.businesswire.com. June 13, 2016.
  9. ^ Lee MK, Kim SG, Watkins E, Moon MK, Rhee SY, Frias JP, et al. (May 2020). "A novel non-PPARgamma insulin sensitizer: MLR-1023 clinicalproof-of-concept in type 2 diabetes mellitus". Journal of Diabetes and Its Complications. 34 (5): 107555. doi:10.1016/j.jdiacomp.2020.107555. PMID 32019723. S2CID 211036334.
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