title: Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition.
abstract: The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Pkwy. W., Chesterfield, MO 63017, USA. kevin.d.jerome@pfizer.com
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Jerome
authors.forename: Paul V
authors.initials: PV
authors.lastname: Rucker
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Huey S
authors.initials: HS
authors.lastname: Shieh
authors.forename: John E
authors.initials: JE
authors.lastname: Baldus
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: John F
authors.initials: JF
authors.lastname: Braganza
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D048051:p38 Mitogen-Activated Protein Kinases