The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

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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.

Rate constants for the reaction of a series of N-phenylnaphth-I -ylamines and some related nitroxides and hydroxylamines with t-alkylperoxyl radicals have been measured using kinetic e.s.r. spectrometry and activation energies and A factors have been derived. The stoicheiometry of the reaction (peroxyl radical to N-phenylnaphth-1 -ylamine) has been shown to be ca. 2 in all cases.Aromatic amines (AH) are used as antioxidants to protect organic materials against atmospheric They react with chain-propagating alkylperoxyl radicals (ROO.) by rapid intermolecular hydrogen exchange (i) to form a free radical (A*) which does not propagate the chain.

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