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

Chemical & Pharmaceutical Bulletin
Yoichi KadohEiji Kawanishi

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-flu...Continue Reading

References

Mar 25, 2005·The European Journal of Neuroscience·Joshua S RodeferMark G Baxter
Feb 20, 2007·Circulation Research·Kenji Omori, Jun Kotera
Oct 5, 2007·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·Andrea L O HebbEileen M Denovan-Wright
Jul 28, 2012·Journal of Medicinal Chemistry·Thomas A ChappieXinjun Hou

❮ Previous
Next ❯

Citations

Jun 13, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Chia George HsuChen Yan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here

Basal Forebrain & Food Avoidance

Neurons in the basal forebrain play specific roles in regulating feeding. Here are the latest discoveries pertaining to the basal forebrain and food avoidance.