title: Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase.
abstract: A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Research and Development Center, 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. derek.cogan@boehringer-ingelheim.com
authors.forename: D A
authors.initials: DA
authors.lastname: Cogan
authors.forename: R
authors.initials: R
authors.lastname: Aungst
authors.forename: E C
authors.initials: EC
authors.lastname: Breinlinger
authors.forename: T
authors.initials: T
authors.lastname: Fadra
authors.forename: D R
authors.initials: DR
authors.lastname: Goldberg
authors.forename: M H
authors.initials: MH
authors.lastname: Hao
authors.forename: R
authors.initials: R
authors.lastname: Kroe
authors.forename: N
authors.initials: N
authors.lastname: Moss
authors.forename: C
authors.initials: C
authors.lastname: Pargellis
authors.forename: K C
authors.initials: KC
authors.lastname: Qian
authors.forename: A D
authors.initials: AD
authors.lastname: Swinamer
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D048051:p38 Mitogen-Activated Protein Kinases