2024-03-29T11:25:20Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/735512021-12-27T16:15:37Zcom_10261_105com_10261_1com_10261_81com_10261_5col_10261_358col_10261_334
Identification in silico and experimental validation of novel phosphodiesterase 7 inhibitors with efficacy in experimental autoimmune encephalomyelitis mice
Redondo, Miriam
Palomo, Valle
Pérez Fernández, Daniel Ignacio
Martín-Álvarez, Rocío
Pérez, Concepción
Paul-Fernández, Nuria
Conde, Santiago
Mengod Los Arcos, Guadalupe
Martínez, Ana
Gil, Carmen
Campillo, Nuria E.
El pdf del artículo es el manuscrito de autor.-- et al.
A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis. © 2012 American Chemical Society.
The authors gratefully acknowledge the financial support of Ministry of Science and Innovation (MICINN) projects nos. SAF2009-13015-C02-01, SAF2009-13015-C02-02, PI10-01874 and CTQ2009-07664; Instituto de Salud Carlos III (ISCiii) projects RD07/0060/0015 (RETICS program) and CIBERNED; Fundación Española para la Ciencia y la Tecnología (FECYT) project no. FCT-09-INC-0367; Programa de cooperación bilateral CSIC-Universidad de la República (2009UY0006).
Peer Reviewed
2013-04-04T07:45:44Z
2013-04-04T07:45:44Z
2012
2013-04-04T07:45:45Z
artículo
http://purl.org/coar/resource_type/c_6501
doi: 10.1021/cn300105c
issn: 1948-7193
ACS Chemical Neuroscience 3(10): 793-803 (2012)
http://hdl.handle.net/10261/73551
10.1021/cn300105c
23077723
en
http://dx.doi.org/10.1021/cn300105c
open
American Chemical Society