| Title: | Gamma Secretase Modulators | ||
| Application Number: | WO 2013066740A1 | Publication date: | 10 May 2013 |
| Priority Application: | 61/553,384 | Priority date: | 31 October 2011 |
| Inventors: | W. Greenlee, D. Pissarnitski, Z. Zhao, Z. Zhu | ||
| Assignee Company: | Merck Sharpe & Dohme | ||
| Disease Area: | Neurodegeneration | Biological Target: | Gamma secretase |
| Summary: | Gamma secretase is an aspartic protease complex involved in the biosynthesis of Aβ peptide, a potential neurotoxic contributor in the progression of Alzheimer’s disease. Direct inhibition of enzymatic activity introduces potential selectivity issues associated with other biological functions of gamma secretase including Notch and Eph processing. As an alternative approach to gamma secretase inhibition, modulation of enzyme activity using, e.g., NSAIDs is a potentially druggable concept. This patent describes the synthesis and evaluation of a novel chemical series that demonstrates inhibition of gamma secretase activity in vitro and reduction of Aβ42 CSF levels following oral administration of a standard dose of 30 mg/kg. | ||
| Primary Markush: |  |
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| Notable Substructures: |  |
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| Biological Data: | Compound A: Aβ42 IC50 39 nM; reduction CSF Aβ42 in vivo, 58% | ||
| Compound B: Aβ42 IC50 190 nM; reduction CSF Aβ42 in vivo, 20% | |||
| Compound C: Aβ42 IC50 29 nM; reduction CSF Aβ42 in vivo, 20% | |||
The authors declare no competing financial interest.