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

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

doi:10.1016/j.bmcl.2011.04.077

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. Epub 2011 Apr 24.

Authors

Allen J Duplantier¹, 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

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.

MeSH terms

Administration, Oral
Animals
Antirheumatic Agents / chemical synthesis
Antirheumatic Agents / chemistry
Antirheumatic Agents / pharmacokinetics
Antirheumatic Agents / pharmacology
Benzamides* / chemical synthesis
Benzamides* / chemistry
Benzamides* / pharmacokinetics
Benzamides* / pharmacology
Drug Discovery*
Humans
Inhibitory Concentration 50
Molecular Structure
Protein Binding / drug effects
Purinergic P2 Receptor Antagonists* / chemical synthesis
Purinergic P2 Receptor Antagonists* / chemistry
Purinergic P2 Receptor Antagonists* / pharmacokinetics
Purinergic P2 Receptor Antagonists* / pharmacology
Rats
Receptors, Purinergic P2X7 / metabolism*
Structure-Activity Relationship
Uracil / analogs & derivatives*
Uracil / chemical synthesis
Uracil / chemistry
Uracil / pharmacokinetics
Uracil / pharmacology

Substances

Antirheumatic Agents
Benzamides
CE 224,535
Purinergic P2 Receptor Antagonists
Receptors, Purinergic P2X7
Uracil
azauracil