Discovery of a potent, selective, and orally active phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia.
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.
Neuroscience Medicinal Chemistry and ‡Discovery Sciences Analytical Sciences, Janssen Research & Development , Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.
José Manuel
JM
Bartolomé-Nebreda
Francisca
F
Delgado
María Luz
ML
Martín-Martín
Carlos M
CM
Martínez-Viturro
Joaquín
J
Pastor
Han Min
HM
Tong
Laura
L
Iturrino
Gregor J
GJ
Macdonald
Wendy
W
Sanderson
Anton
A
Megens
Xavier
X
Langlois
Marijke
M
Somers
Greet
G
Vanhoof
Susana
S
Conde-Ceide
D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases