2. Academic Validation
  3. Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists

Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists

  • ACS Med Chem Lett. 2010 May 14;1(7):316-20. doi: 10.1021/ml100077x.
Jian Jin 1,  Angel Morales-Ramos 1,  Patrick Eidam 1,  John Mecom 1,  Yue Li 1,  Carl Brooks 1,  Mark Hilfiker 1,  David Zhang 1,  Ning Wang 1,  Dongchuan Shi 1,  Pei-San Tseng 1,  Karen Wheless 1,  Brian Budzik 1,  Karen Evans 1,  Jon-Paul Jaworski 1,  Jack Jugus 1,  Lisa Leon 1,  Charlene Wu 1,  Mark Pullen 1,  Bhumika Karamshi 1,  Parvathi Rao 1,  Emma Ward 1,  Nicholas Laping 1,  Christopher Evans 1,  Colin Leach 1,  Dennis Holt 1,  Xin Su 1,  Dwight Morrow 1,  Harvey Fries 1,  Kevin Thorneloe 1,  Richard Edwards 1
Affiliations

Affiliation

  • 1 GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406.
PMID: 24900213 DOI: 10.1021/ml100077x
Abstract

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.

Keywords

3-oxazolidinedione-6-aryl-pyridinones; EP3 receptor; novel, potent, selective, and orally active antagonists.

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