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ID: ALA1777794
Journal: Bioorg Med Chem Lett
Title: 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.
Authors: Duplantier AJ, Dombroski MA, Subramanyam C, Beaulieu AM, Chang SP, Gabel CA, Jordan C, Kalgutkar AS, Kraus KG, Labasi JM, Mussari C, Perregaux DG, Shepard R, Taylor TJ, Trevena KA, Whitney-Pickett C, Yoon K.
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.
CiteXplore: 21565499