Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.
Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
Höfgen
Norbert
N
Biotie Therapies GmbH, Meissner Strasse 191, 01445 Radebeul, Germany. norbert.hoefgen@biotie.com
Stange
Hans
H
Schindler
Rudolf
R
Lankau
Hans-Joachim
HJ
Grunwald
Christian
C
Langen
Barbara
B
Egerland
Ute
U
Tremmel
Peter
P
Pangalos
Menelas N
MN
Marquis
Karen L
KL
Hage
Thorsten
T
Harrison
Boyd L
BL
Malamas
Michael S
MS
Brandon
Nicholas J
NJ
Kronbach
Thomas
T
D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar
D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases