1,4-CYCLOHEXANECARBOXYLATES - POTENT AND SELECTIVE INHIBITORS OF PHOSPHODIESTERASE-4 FOR THE TREATMENT OF ASTHMA

Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [H-3]rolipram-binding sites in the central nervous system. U se of this strategy led ultimately to the identification of -[3-(cyclo pentyloxy)-4-methoxyphenyl]cyclohexane-1 -carboxylic acid (1, SB 20749 9, Ariflo(TM)), a potent second-generation inhibitor of PDE4 with a de creased potential for side effects versus the archetypic first generat ion inhibitor, (R)-rolipram.