Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.
Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. izzat_raheem@merck.com
Izzat T
IT
Raheem
Michael J
MJ
Breslin
Christine
C
Fandozzi
Joy
J
Fuerst
Nicole
N
Hill
Sarah
S
Huszar
Monika
M
Kandebo
Somang H
SH
Kim
Bennett
B
Ma
Georgia
G
McGaughey
John J
JJ
Renger
John D
JD
Schreier
Sujata
S
Sharma
Sean
S
Smith
Jason
J
Uslaner
Youwei
Y
Yan
Paul J
PJ
Coleman
Christopher D
CD
Cox
D000284:Administration, Oral; D000818:Animals; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP