Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase.
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.
Cogan
D A
DA
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
Aungst
R
R
Breinlinger
E C
EC
Fadra
T
T
Goldberg
D R
DR
Hao
M H
MH
Kroe
R
R
Moss
N
N
Pargellis
C
C
Qian
K C
KC
Swinamer
A D
AD
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*
D004791:Enzyme Inhibitors; D014230:Triazoles; D048051:p38 Mitogen-Activated Protein Kinases