Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase

  • Bioorg Med Chem Lett. 2008 Jun 1;18(11):3251-5. doi: 10.1016/j.bmcl.2008.04.043.
D A Cogan  1 ,  R Aungst ,  E C Breinlinger ,  T Fadra ,  D R Goldberg ,  M H Hao ,  R Kroe ,  N Moss ,  C Pargellis ,  K C Qian ,  A D Swinamer
Affiliations
  • 1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Research and Development Center, 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. [email protected]
PMID: 18462940 DOI: 10.1016/j.bmcl.2008.04.043
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.