Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
Macdonald
Dwight
D
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. dwight_macdonald@merck.com
Mastracchio
Anthony
A
Perrier
Hélène
H
Dubé
Daniel
D
Gallant
Michel
M
Lacombe
Patrick
P
Deschênes
Denis
D
Roy
Bruno
B
Scheigetz
John
J
Bateman
Kevin
K
Li
Chun
C
Trimble
Laird A
LA
Day
Stephen
S
Chauret
Nathalie
N
Nicoll-Griffith
Deborah A
DA
Silva
Jose M
JM
Huang
Zheng
Z
Laliberté
France
F
Liu
Susana
S
Ethier
Diane
D
Pon
Doug
D
Muise
Eric
E
Boulet
Louise
L
Chan
Chi Chung
CC
Styhler
Angela
A
Charleson
Stella
S
Mancini
Joseph
J
Masson
Paul
P
Claveau
David
D
Nicholson
Donald
D
Turner
Mervyn
M
Young
Robert N
RN
Girard
Yves
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012453:Saimiri; D012756:Sheep; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
C507187:L-454,560; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4