- 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.
Bioorganic & medicinal chemistry letters (2011-05-14)
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
PMID21565499
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.
MATERIALS