Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors.
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Lacombe
Patrick
P
Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada. patrick_lacombe@merck.com
Chauret
Nathalie
N
Claveau
David
D
Day
Stephen
S
Deschênes
Denis
D
Dubé
Daniel
D
Gallant
Michel
M
Girard
Yves
Y
Huang
Zheng
Z
Laliberté
France
F
Lévesque
Jean-Francois
JF
Liu
Susana
S
Macdonald
Dwight
D
Mancini
Joseph A
JA
Masson
Paul
P
Nicholson
Donald W
DW
Nicoll-Griffith
Deborah A
DA
Salem
Myriam
M
Styhler
Angela
A
Young
Robert N
RN
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D006168:Guinea Pigs; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012453:Saimiri; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D010047:Ovalbumin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4