Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535

  • Bioorg Med Chem Lett. 2011 Jun 15;21(12):3708-11. doi: 10.1016/j.bmcl.2011.04.077.
Allen J Duplantier  1 ,  Mark A Dombroski ,  Chakrapani Subramanyam ,  Aimee M Beaulieu ,  Shang-Poa Chang ,  Christopher A Gabel ,  Crystal Jordan ,  Amit S Kalgutkar ,  Kenneth G Kraus ,  Jeff M Labasi ,  Christopher Mussari ,  David G Perregaux ,  Rick Shepard ,  Timothy J Taylor ,  Kristen A Trevena ,  Carrie Whitney-Pickett ,  Kwansik Yoon
Affiliations
  • 1. Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. [email protected]
PMID: 21565499 DOI: 10.1016/j.bmcl.2011.04.077
Abstract

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.

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