title: 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma.
abstract: 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Christensen
authors.forename: A
authors.initials: A
authors.lastname: Guider
authors.forename: C J
authors.initials: CJ
authors.lastname: Forster
authors.forename: J G
authors.initials: JG
authors.lastname: Gleason
authors.forename: P E
authors.initials: PE
authors.lastname: Bender
authors.forename: J M
authors.initials: JM
authors.lastname: Karpinski
authors.forename: W E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: M S
authors.initials: MS
authors.lastname: Barnette
authors.forename: D C
authors.initials: DC
authors.lastname: Underwood
authors.forename: D E
authors.initials: DE
authors.lastname: Griswold
authors.forename: L B
authors.initials: LB
authors.lastname: Cieslinski
authors.forename: M
authors.initials: M
authors.lastname: Burman
authors.forename: S
authors.initials: S
authors.lastname: Bochnowicz
authors.forename: R R
authors.initials: RR
authors.lastname: Osborn
authors.forename: C D
authors.initials: CD
authors.lastname: Manning
authors.forename: M
authors.initials: M
authors.lastname: Grous
authors.forename: L M
authors.initials: LM
authors.lastname: Hillegas
authors.forename: J O
authors.initials: JO
authors.lastname: Bartus
authors.forename: M D
authors.initials: MD
authors.lastname: Ryan
authors.forename: D S
authors.initials: DS
authors.lastname: Eggleston
authors.forename: R C
authors.initials: RC
authors.lastname: Haltiwanger
authors.forename: T J
authors.initials: TJ
authors.lastname: Torphy
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D020889:Rolipram; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram