2. Academic Validation
  3. Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

  • Bioorg Med Chem Lett. 2010 Nov 15;20(22):6387-93. doi: 10.1016/j.bmcl.2010.09.087.
Michel Gallant 1,  Renee Aspiotis,  Stephen Day,  Rebecca Dias,  Daniel Dubé,  Laurence Dubé,  Richard W Friesen,  Mario Girard,  Daniel Guay,  Pierre Hamel,  Zheng Huang,  Patrick Lacombe,  Sebastien Laliberté,  Jean-François Lévesque,  Susana Liu,  Dwight Macdonald,  Joseph Mancini,  Donald W Nicholson,  Angela Styhler,  Karen Townson,  Kerry Waters,  Robert N Young,  Yves Girard
Affiliations

Affiliation

  • 1 Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada H9H3L1. michel_gallant@merck.com
PMID: 20933411 DOI: 10.1016/j.bmcl.2010.09.087
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.

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