Back to Search
Start Over
Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor
- Source :
- Chemical and Pharmaceutical Bulletin. 66:243-250
- Publication Year :
- 2018
- Publisher :
- Pharmaceutical Society of Japan, 2018.
-
Abstract
- Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.
- Subjects :
- 0301 basic medicine
Pyrimidine
Hydrochloride
Stereochemistry
Phosphodiesterase
General Chemistry
General Medicine
Medium spiny neuron
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Quinoxaline
chemistry
Pyran
Drug Discovery
Structure–activity relationship
PDE10A
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 13475223 and 00092363
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Chemical and Pharmaceutical Bulletin
- Accession number :
- edsair.doi...........e6843e881235274aefe3a3c26a35ba5a