Abstract

We present the in vitro pharmacology of a novel adenosine 3'-5' -cyclic monophosphate-specific phosphodiesterase (PDE) type 4 inhibitor, CP-80633 ((2'S)5-[3-(2' -exobicyclo[2.2.1]-heptyloxy)4-methoxyphenyl] tetrahydro-2(1H)-primidone), which has shown efficacy in phase II clinical trials for atopic dermatitis. CP-80633 inhibits PDE4 isozymes (human lung IC50 = 1.27 microM) in the absence of effects on PDE1, PDE2, PDE3 and PDE5 isozymes (IC50 > 100 microM). It exhibits no significant selectivity for any single cloned PDE4A, B, C or D isoform. CP-80633 inhibits adenosine 3'-5'-cyclic monophosphate hydrolysis in partially purified human peripheral blood monocyte cytosol (IC50 = 3.52 microM), eosinophil membrane (IC50 = 1.10 microM) and T cell membrane (IC50 = 2.28 microM) preparations. Inhibition of eosinophil PDE4 adenosine 3'-5'-cyclic mono-phosphate hydrolysis by CP-80,633 occurs in a noncompetitive manner. Unlike theophylline, CP-80,633 is inactive against ratrain adenosine (A1,A2) receptors. Consistent with its action as a PDE4 inhibitor in whole cells, CP-80633 potentiates PGE1 dependent increases in adenosine 3'-5'-cyclic monophosphate levels in human U937 cells, and in human eosinophils, monocytes and T cells (EC200 approximately 1.0 microM). Consequently, CP-80633 inhibits many inflammatory cell functions including 1) human eosinophil superoxide anion production (IC50 < 0.6 microM), 2 C5a-(IC50 = 0.40 microM) and LTB4-(IC50 = 0.20 microM) mediated guinea pig peritoneal eosinophil chemotaxis and 3) lipopolysac-charide-induced tumor necrosis factor-alpha release from human monocytes (IC50 = 0.219 microM). These data clearly demonstrate that CP-80633 is a selective inhibitor of PDE4 isozymes, and support its potential use as a therapeutic agent for a number of inflammatory and immune disorders.