Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment
| Autor: | Laurence Dube, Richard Friesen, Karen Townson, Daniel Dube, Jean-François Lévesque, Susana Liu, Michel Gallant, Dwight Macdonald, Donald W. Nicholson, Zheng Huang, Renee Aspiotis, Rebecca Dias, Sebastien Laliberte, Patrick Lacombe, Pierre Hamel, Daniel Guay, Kerry A. Waters, Mario Girard, Joseph A. Mancini, Stephen Day, Robert N. Young, Angela Styhler, Yves Girard |
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| Rok vydání: | 2010 |
| Předmět: |
Cyclopropanes
Male Memory Long-Term Phosphodiesterase Inhibitors Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry Heterocyclic Compounds 2-Ring Structure-Activity Relationship Dogs In vivo Drug Discovery Structure–activity relationship Animals Humans PDE4 Inhibitors Adverse effect Cognitive impairment Molecular Biology Whole blood Chemistry Organic Chemistry Phosphodiesterase Long-term memory loss Macaca mulatta Cyclic Nucleotide Phosphodiesterases Type 4 Rats Molecular Medicine Female Cognition Disorders |
| Zdroj: | Bioorganicmedicinal chemistry letters. 20(22) |
| ISSN: | 1464-3405 |
| Popis: | The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis. |
| Databáze: | OpenAIRE |
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