Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening
- Bioorg Med Chem Lett. 2013 Oct 15;23(20):5740-3. doi: 10.1016/j.bmcl.2013.07.067.
- 1. Department of Medicinal Chemistry, Piramal Enterprises Limited, 1, Nirlon Complex, Goregaon (E), Mumbai, India. Electronic address: [email protected].
With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of Insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl-phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07±0.02 μM) in differentiated skeletal muscle cells in presence of Insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.