Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding.
A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated.
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, H9R 4P8, Québec, Canada. nathalie_chauret@merk.com
Nathalie
N
Chauret
Daniel
D
Guay
Chun
C
Li
Stephen
S
Day
José
J
Silva
Marc
M
Blouin
Yves
Y
Ducharme
James A
JA
Yergey
Deborah A
DA
Nicoll-Griffith
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002396:Catechols / Q000737:chemistry*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D002396:Catechols; D011725:Pyridines; C102660:CDP 840; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C034221:catechol