Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

J Med Chem. 2015 Sep 10;58(17):6747-52. doi: 10.1021/acs.jmedchem.5b00902. Epub 2015 Aug 28.

Abstract

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

MeSH terms

  • Animals
  • Cyclohexanecarboxylic Acids / chemistry*
  • Cyclohexanecarboxylic Acids / pharmacokinetics
  • Cyclohexanecarboxylic Acids / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Naphthyridines / chemistry*
  • Naphthyridines / pharmacokinetics
  • Naphthyridines / pharmacology
  • Nausea / chemically induced
  • Phosphodiesterase 4 Inhibitors / chemistry*
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Thermodynamics
  • Vomiting / chemically induced

Substances

  • 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)cyclohexanecarboxylic acid
  • Cyclohexanecarboxylic Acids
  • Naphthyridines
  • Phosphodiesterase 4 Inhibitors