Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice
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- 作者：Miriam Redondo ; Valle Palomo ; Jos茅 Brea ; Daniel I. P茅rez ; Roc铆o Mart铆n-脕lvarez ; Concepci贸n P茅rez ; Nuria Pa煤l-Fern谩ndez ; Santiago Conde ; Mar铆a Isabel Cadavid ; Mar铆a Isabel Loza ; Guadalupe Mengod ; Ana Mart铆nez ; Carmen Gil ; Nuria E. Campillo
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：October 17, 2012
- 年：2012
- 卷：3
- 期：10
- 页码：793-803
- 全文大小：389K
- 年卷期：v.3,no.10(October 17, 2012)
- ISSN：1948-7193
文摘
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.