Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship

  • Bioorg Med Chem. 2011 Feb 1;19(3):1242-55. doi: 10.1016/j.bmc.2010.12.027.
Jin Xie  1 ,  Gennadiy I Poda ,  Yiding Hu ,  Natalie X Chen ,  Richard F Heier ,  Serge G Wolfson ,  Matthew T Reding ,  Patrick J Lennon ,  Ravi G Kurumbail ,  Shaun R Selness ,  Xiong Li ,  Nandini N Kishore ,  Cynthia D Sommers ,  Lori Christine ,  Sheri L Bonar ,  Neetu Venkatraman ,  Sumathy Mathialagan ,  Sarah J Brustkern ,  Horng-Chih Huang
Affiliations
  • 1. Department of Medicinal Chemistry, Pfizer Inc., 700 Chesterfield Parkway West, St. Louis, MO 63017, USA. [email protected]
PMID: 21236687 DOI: 10.1016/j.bmc.2010.12.027
Abstract

Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing Enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).