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Christensen SB. Guider A. Forster CJ. Gleason JG. Bender PE. Karpinski JM. DeWolf WE Jr. Barnette MS. Underwood DC. Griswold DE. Cieslinski LB. Burman M. Bochnowicz S. Osborn RR. Manning CD. Grous M. Hillegas LM. Bartus JO. Ryan MD. Eggleston DS. Haltiwan
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
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 [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.