Optimization and structure-activity relationship of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: identification of MK-0873, a potent and effective PDE4 inhibitor

  • Bioorg Med Chem Lett. 2008 Oct 15;18(20):5554-8. doi: 10.1016/j.bmcl.2008.09.009.
Daniel Guay  1 ,  Louise Boulet ,  Richard W Friesen ,  Mario Girard ,  Pierre Hamel ,  Zheng Huang ,  France Laliberté ,  Sébastien Laliberté ,  Joseph A Mancini ,  Eric Muise ,  Doug Pon ,  Angela Styhler
Affiliations
  • 1. Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. [email protected]
PMID: 18835163 DOI: 10.1016/j.bmcl.2008.09.009
Abstract

A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-alpha in human whole blood and minimizing affinity for the hERG Potassium Channel. From these studies, compounds 18 and 20 (MK-0873) were identified as optimized PDE4 inhibitors with good overall in vitro and in vivo profiles and selected as development candidates.

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