N-arylrolipram derivatives as potent and selective PDE4 inhibitors.
Derivatization of rolipram led to the identification of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-5-( 3- methoxybenzyloxy)-benzoic acid N',N'-dimethylhydrazide (4), a potent and selective inhibitor of PDE4, which inhibits the activation of human leukocytes with pIC50 values in the range of 7.3-7.8, and blocks antigen induced eosinophilia in Brown Norway rats at a dose of 1 mg/kg (i.t.).
Bacher
E
E
Respiratory Disease Therapeutic Area, Novartis Horsham Research Center, West Sussex, UK.
Boer
C
C
Bray-French
K
K
Demnitz
F W
FW
Keller
T H
TH
Mazzoni
L
L
Müller
T
T
Walker
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D020889:Rolipram; D013329:Structure-Activity Relationship
D018927:Anti-Asthmatic Agents; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram