Design, synthesis, and biological evaluation of 8-biarylquinolines: a novel class of PDE4 inhibitors.
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
Gallant
Michel
M
Merck Frosst Center for Therapeutic Research, Department of Medicinal Chemistry, PO Box 1005, Pointe Claire-Dorval, Que., Canada.
Chauret
Nathalie
N
Claveau
David
D
Day
Stephen
S
Deschênes
Denis
D
Dubé
Daniel
D
Huang
Zheng
Z
Lacombe
Patrick
P
Laliberté
France
F
Lévesque
Jean-François
JF
Liu
Susana
S
Macdonald
Dwight
D
Mancini
Joseph
J
Masson
Paul
P
Mastracchio
Anthony
A
Nicholson
Donald
D
Nicoll-Griffith
Deborah A
DA
Perrier
Hélène
H
Salem
Myriam
M
Styhler
Angela
A
Young
Robert N
RN
Girard
Yves
Y
D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011804:Quinolines