1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 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 [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.
Christensen
S B
SB
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Guider
A
A
Forster
C J
CJ
Gleason
J G
JG
Bender
P E
PE
Karpinski
J M
JM
DeWolf
W E
WE
Barnette
M S
MS
Underwood
D C
DC
Griswold
D E
DE
Cieslinski
L B
LB
Burman
M
M
Bochnowicz
S
S
Osborn
R R
RR
Manning
C D
CD
Grous
M
M
Hillegas
L M
LM
Bartus
J O
JO
Ryan
M D
MD
Eggleston
D S
DS
Haltiwanger
R C
RC
Torphy
T J
TJ
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
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