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.
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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. allen.j.duplantier@pfizer.com
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dombroski
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Beaulieu
authors.forename: Shang-Poa
authors.initials: SP
authors.lastname: Chang
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gabel
authors.forename: Crystal
authors.initials: C
authors.lastname: Jordan
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Kraus
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Labasi
authors.forename: Christopher
authors.initials: C
authors.lastname: Mussari
authors.forename: David G
authors.initials: DG
authors.lastname: Perregaux
authors.forename: Rick
authors.initials: R
authors.lastname: Shepard
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Taylor
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Trevena
authors.forename: Carrie
authors.initials: C
authors.lastname: Whitney-Pickett
authors.forename: Kwansik
authors.initials: K
authors.lastname: Yoon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; D001549:Benzamides; C562356:CE 224,535; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D014498:Uracil; C100248:azauracil