Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening

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Abstract

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.

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Acknowledgements

The authors wish to thank Dr. Somesh Sharma, Dr. Rajiv Sharma, Dr. Veena Agarwal and Dr. Arun Balakrishnan of Piramal Enterprises Limited, India for supporting this study and providing the infrastructure needed for carrying out the research work reported in this Letter. We also thank Mr. T.T. Matan and Mr. S. Senthil Kumar for their excellent technical support.

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