Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

Nathalie Chauret; Daniel Guay; Chun Li; Stephen Day; José Silva; Marc Blouin; Yves Ducharme; James A Yergey; Deborah A Nicoll-Griffith

doi:10.1016/s0960-894x(02)00349-9

Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding

Bioorg Med Chem Lett. 2002 Aug 19;12(16):2149-52. doi: 10.1016/s0960-894x(02)00349-9.

Authors

Nathalie Chauret¹, Daniel Guay, Chun Li, Stephen Day, José Silva, Marc Blouin, Yves Ducharme, James A Yergey, Deborah A Nicoll-Griffith

Affiliation

¹ Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, H9R 4P8, Québec, Canada. [email protected]

PMID: 12127525
DOI: 10.1016/s0960-894x(02)00349-9

Abstract

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.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Animals
Catechols / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Protein Binding
Pyridines / chemistry*
Pyridines / metabolism
Pyridines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Catechols
Pyridines
CDP 840
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 4
catechol