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ID: ALA1799977
Journal: Bioorg Med Chem Lett
Title: Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.
Authors: Gallant M, Aspiotis R, Day S, Dias R, Dubé D, Dubé L, Friesen RW, Girard M, Guay D, Hamel P, Huang Z, Lacombe P, Laliberté S, Lévesque JF, Liu S, Macdonald D, Mancini J, Nicholson DW, Styhler A, Townson K, Waters K, Young RN, Girard Y.
Abstract: 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.
CiteXplore: 20933411