Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors

Li Xing; Bruce C Hamper; Theresa R Fletcher; Jay M Wendling; Jeffery Carter; James K Gierse; Subo Liao

doi:10.1016/j.bmcl.2010.12.023

Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors

Bioorg Med Chem Lett. 2011 Feb 1;21(3):993-6. doi: 10.1016/j.bmcl.2010.12.023. Epub 2010 Dec 10.

Authors

Li Xing¹, Bruce C Hamper, Theresa R Fletcher, Jay M Wendling, Jeffery Carter, James K Gierse, Subo Liao

Affiliation

¹ Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, MO 63017, USA.

PMID: 21215625
DOI: 10.1016/j.bmcl.2010.12.023

Abstract

Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.

MeSH terms

Animals
Benzopyrans / chemical synthesis
Benzopyrans / chemistry*
Benzopyrans / pharmacology
Chemistry, Pharmaceutical
Cyclooxygenase 2 / chemistry*
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry*
Cyclooxygenase 2 Inhibitors / pharmacology
Humans
Microsomes / metabolism*
Protein Binding
Rats
Structure-Activity Relationship
Thermodynamics

Substances

Benzopyrans
Cyclooxygenase 2 Inhibitors
SD 8381
Cyclooxygenase 2