Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors.
A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.
Pascal
Y
Y
Institut de Recherche Jouveinal-Parke Davis, Fresnes, France. yves.pascal@wl.com
Andrianjara
C R
CR
Auclair
E
E
Avenel
N
N
Bertin
B
B
Calvet
A
A
Féru
F
F
Lardon
S
S
Moodley
I
I
Ouagued
M
M
Payne
A
A
Pruniaux
M P
MP
Szilagyi
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D020889:Rolipram / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020298:U937 Cells
D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D001569:Benzodiazepines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram