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

• Published in: Chemical & pharmaceutical bulletin Vol. 66; no. 3; pp. 243 - 250
• Main Authors: Kadoh, Yoichi, Miyoshi, Haruko, Matsumura, Takehiko, Tanaka, Yoshihito, Hongu, Mitsuya, Kimura, Mayumi, Takedomi, Kei, Omori, Kenji, Kotera, Jun, Sasaki, Takashi, Kobayashi, Tamaki, Taniguchi, Hiroyuki, Watanabe, Yumi, Kojima, Koki, Sakamoto, Toshiaki, Himiyama, Toshiyuki, Kawanishi, Eiji
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2018; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; Avoidance behavior; Avoidance Learning - drug effects; Binding Sites; Brain; conditioned avoidance response (CAR); Conditioning; Crystallography, X-Ray; Cyclic AMP; Cyclic GMP; Drug Evaluation, Preclinical; Erectile dysfunction; Homology; Hydrolase; Inhibitors; Inhibitory Concentration 50; Mental disorders; Molecular Dynamics Simulation; Neostriatum; Neurons; Optimization; Penetration; Pharmacokinetics; Pharmacology; Phosphodiesterase; phosphodiesterase (PDE) 10A; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - metabolism; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Psychosis; pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Quinoxaline; Quinoxalines; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Rats; Rodents; Schizophrenia; Signs and symptoms; Spiny neurons; Stilbene; Structure-Activity Relationship; Tetrahydro-2H-pyran; conditioned avoidance response (CAR); stilbene; quinoxaline; schizophrenia; pyrimidine; phosphodiesterase (PDE) 10A
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c17-00783

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.