| Autor: |
Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M; Anatomy Department, School of Medicine, University of Navarra , Irunlarrea 1, E-31008 Pamplona, Spain., de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T; WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China., Wei W; WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China., Musheng X; WuXi Apptec (Tianjin) Co. Ltd., TEDA, No. 111 HuangHai Road, Fourth Avenue, Tianjin 300456, PR China., Garcia-Osta A, Oyarzabal J |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2016 Oct 13; Vol. 59 (19), pp. 8967-9004. Date of Electronic Publication: 2016 Sep 27. |
| DOI: |
10.1021/acs.jmedchem.6b00908 |
| Abstrakt: |
Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's 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 ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ). |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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