Identification in silico and experimental validation of novel phosphodiesterase 7 inhibitors with efficacy in experimental autoimmune encephalomyelitis mice.
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.
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Miriam
M
Redondo
Valle
V
Palomo
José
J
Brea
Daniel I
DI
Pérez
Rocío
R
Martín-Álvarez
Concepción
C
Pérez
Nuria
N
Paúl-Fernández
Santiago
S
Conde
María Isabel
MI
Cadavid
María Isabel
MI
Loza
Guadalupe
G
Mengod
Ana
A
Martínez
Carmen
C
Gil
Nuria E
NE
Campillo
D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D016896:Treatment Outcome
D010726:Phosphodiesterase Inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse