Tolimidone Explained

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]} 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.^[3] The company proceeded to show that MLR-1023 is an allosteric activator of Lyn kinase with an EC50 of 63 nM.^{[4] [5]} As of 2012 Melior was repurposing it for diabetes.^{[6] [7]} In June 2016, the company reported positive results from their Phase 2a clinical study in diabetic subjects^{[8] [9]}

Notes and References

1. Web site: Tolimidone. Springer Nature Switzerland AG . AdisInsight. 26 August 2017. en.
2. Lipinski CA, Stam JG, Pereira JN, Ackerman NR, Hess HJ . Bronchodilator and antiulcer phenoxypyrimidinones . Journal of Medicinal Chemistry . 23 . 9 . 1026–1031 . September 1980 . 7411545 . 10.1021/jm00183a012 . Compound 3 has been assigned the nonproprietary (USAN) name tolimidone .
3. Lipinski CA, Reaume AG . 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 . May 2020 . 32201192 . 10.1016/j.bmc.2020.115425 . free .
4. Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS . 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 . July 2012 . 22431203 . 10.1124/jpet.112.192187 . 7288053 .
5. Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG . 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 . July 2012 . 22473614 . 10.1124/jpet.112.192096 . 26419896 .
6. Book: Saporito MS, Lipinski CA, Reaume AG . Barratt MJ, Frail DE . Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. 2012. John Wiley & Sons. 978-1-118-27439-2. 270. https://books.google.com/books?id=TqOBrx_xZgAC&pg=PA270. en. Chapter 9:Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates.
7. Melior Pharmaceuticals Announces Positive Results in Phase 2B Study with Tolimidone for Type 2 Diabetes. 14 May 2019.
8. Web site: Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study. June 13, 2016. www.businesswire.com.
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 . 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 . May 2020 . 32019723 . 10.1016/j.jdiacomp.2020.107555 . 211036334 .