title: Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors.
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.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, MO 63017, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Hamper
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Fletcher
authors.forename: Jay M
authors.initials: JM
authors.lastname: Wendling
authors.forename: Jeffery
authors.initials: J
authors.lastname: Carter
authors.forename: James K
authors.initials: JK
authors.lastname: Gierse
authors.forename: Subo
authors.initials: S
authors.lastname: Liao
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008861:Microsomes / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001578:Benzopyrans; D052246:Cyclooxygenase 2 Inhibitors; C557877:SD 8381; D051546:Cyclooxygenase 2