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.
Chauret
Nathalie
N
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, H9R 4P8, Québec, Canada. nathalie_chauret@merk.com
Guay
Daniel
D
Li
Chun
C
Day
Stephen
S
Silva
José
J
Blouin
Marc
M
Ducharme
Yves
Y
Yergey
James A
JA
Nicoll-Griffith
Deborah A
DA
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