The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors.
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.
Aspiotis
Renee
R
Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy, Kirkland, Québec., Canada H9H 3L1. renee_aspiotis@merck.com
Deschênes
Denis
D
Dubé
Daniel
D
Girard
Yves
Y
Huang
Zheng
Z
Laliberté
France
F
Liu
Susana
S
Papp
Robert
R
Nicholson
Donald W
DW
Young
Robert N
RN
D000818:Animals; D001249:Asthma / Q000188:drug therapy; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4