Identification of 2,3-disubstituted pyridines as potent, non-emetic PDE4 inhibitors

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2689-92. doi: 10.1016/j.bmcl.2014.04.052. Epub 2014 Apr 20.

Abstract

A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis.

Keywords: 2,3-Disubstituted pyridine; Anti-inflammatory agent; PDE4 inhibitors; Phosphodiesterase 4; Structure activity relationship.

MeSH terms

  • Administration, Oral
  • Asthma / drug therapy*
  • Emetics / adverse effects
  • Enzyme Activation / drug effects
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis*
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Emetics
  • Phosphodiesterase 4 Inhibitors
  • Pyridines
  • pyridine