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
  • 1. Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada H9H3L1. [email protected]
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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