JOURNAL ARTICLE

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Izzat T Raheem, Michael J Breslin, Christine Fandozzi, Joy Fuerst, Nicole Hill, Sarah Huszar, Monika Kandebo, Somang H Kim, Bennett Ma, Georgia McGaughey, John J Renger, John D Schreier, Sujata Sharma, Sean Smith, Jason Uslaner, Youwei Yan, Paul J Coleman, Christopher D Cox
Bioorganic & Medicinal Chemistry Letters 2012 September 15, 22 (18): 5903-8
22892116
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
22892116
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"