Bioorganic & Medicinal Chemistry Letters 2011-01-01

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7receptor antagonists leading to the discovery of the clinical candidate CE-224,535

Allen J. Duplantier, 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, Allen J. Duplantier, 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

Index: Bioorg. Med. Chem. Lett. 21(12) , 3708-11, (2011)

Full Text: HTML

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.Copyright © 2011 Elsevier Ltd. All rights reserved.