2. Academic Validation
  3. 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

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

Affiliation

  • 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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