Tolimidone

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]

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

References
  1. Saporito, Michael S.; Lipinski, Christopher A.; Reaume, Andrew G. (2012). "Chapter 9:Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates". In Barratt, Michael J.; Frail, Donald E. (eds.). Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. John Wiley & Sons. p. 270. ISBN 9781118274392.
  2. "Tolimidone". AdisInsight. Retrieved 26 August 2017.
  3. Lipinski, C. A.; Stam, J. G.; Pereira, J. N.; Ackerman, N. R.; Hess, H. J. (1980). "Bronchodilator and antiulcer phenoxypyrimidinones". Journal of Medicinal Chemistry. 23 (9): 1026–31. doi:10.1021/jm00183a012. PMID 7411545. Compound 3 has been assigned the nonproprietary (USAN) name tolimidone
  4. 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". Bioorg Med Chem. 28 (8): 115425. doi:10.1016/j.bmc.2020.115425. PMID 32201192.
  5. Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS (2012). "The Lyn kinase activator MLR-123 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes". J Pharmacol Exp Ther. 342 (1): 23–32. doi:10.1124/jpet.112.192187. PMID 22431203. S2CID 7288053.
  6. Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG (2011). "MLR-1023 is potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo". Journal of Pharmacology and Experimental Therapeutics. 342 (1): 15–22. doi:10.1124/jpet.112.192096. PMID 22473614. S2CID 26419896.
  7. "Melior Discovery website press releases".
  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, Chung CH, Lee SH, Block B, Cha BS, Park HK, Kim BJ, Greenway F (May 2020). "A Novel Non-PPARgamma Insulin Sensitizer: MLR-1023 Clinical Proof-of-concept in Type 2 Diabetes Mellitus". J. Diabetes Complications. 34 (5): 107555. doi:10.1016/j.jdiacomp.2020.107555. PMID 32019723. S2CID 211036334.
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