1.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).
Press NJ1, Taylor RJ1, Fullerton JD1, Tranter P1, McCarthy C1, Keller TH1, Arnold N1, Beer D1, Brown L1, Cheung R1, Christie J1, Denholm A1, Haberthuer S1, Hatto JD1, Keenan M1, Mercer MK1, Oakman H1, Sahri H1, Tuffnell AR1, Tweed M1, Trifilieff A1. J Med Chem. 2015 Sep 10;58(17):6747-52. doi: 10.1021/acs.jmedchem.5b00902. Epub 2015 Aug 28.
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.