Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 19, Pages 8967-9004Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00908
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Funding
- Foundation for Applied Medical Research (FIMA)
- University of Navarra (Pamplona, Spain)
- Fundacion Fuentes Dutor
- Ministerio de Economia y Competitividad (FIS) [PI12/00710]
- FSE (Inncorpora-Torres Quevedo grant) [PTQ-12-05641]
- FIS projects [11/02861, 14/01244]
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Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimers disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing.
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