Discovery of 2-[(<i>E</i>)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-<i>N</i>-(tetrahydro-2<i>H</i>-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor

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.

Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units

“…By an initial medicinal chemistry route as shown in Scheme , quinoxaline ( 7 ) was synthesized from aminonitrobenzene ( 2 ) through a long synthetic sequence of five reactions involving amidation with mono malonic chloride, the quinoxaline- N -oxide formation under basic conditions, reduction of the N -oxide with PBr 3 , chlorination with POCl 3 , and a Pd-catalyzed alkylation of the chloride with PdCl 2 (dppf), which finally required column chromatography purification; therefore, we decided to drastically change the synthetic route for 7 in order to reduce the synthetic steps. Our new synthesis started from readily available 4-fuloro-1,2-diaminobenzene ( 15 ) and ethyl chloroacetyhlacetonate ( 16 ) (Scheme ).…”

“…Among the 11 designated families of PDEs, PDE10A works as a dual substrate enzyme toward both cAMP and cGMP with a higher affinity for cAMP than that for cGMP . To date, PDE10A inhibition has been suggested as a therapeutic strategy for the treatment of patients with various diseases or conditions such as psychotic disorder, anxiety disorder, movement disorder, drug addiction, mood disorder, mood episode, and neurodegenerative disease . Therefore, many pharmaceutical industries have noted its therapeutic possibilities and designed unique compounds as PDE10A inhibitors .…”

“…Therefore, many pharmaceutical industries have noted its therapeutic possibilities and designed unique compounds as PDE10A inhibitors . Our refinement of the series led to the discovery of pyrazolo­[1,5- a ]­pyrimidine ( 1 ), which was ultimately selected as a candidate for further development.…”

“…To provide 1 in quantities required for preclinical and early clinical development efforts, significant improvements in the synthetic route were required to enhance the overall efficiency and throughput. The medicinal chemistry route for 1 comprised 13 reaction steps in the longest linear sequence that utilized column chromatography purification in the early steps and excess amounts of expensive reagents such as monoethyl malonate and ( R )-3-fluoropyrrolidine (Scheme ); therefore, this initial approach had limitations in scaling up the synthesis to multikilograms. Here we describe a scalable synthetic approach that provided multikilogram quantities of the promising candidate 1 .…”

Phosphodiesterase 10A Is a Key Mediator of Lung Inflammation

“…discovered (57). New data (58) suggest that inhibition of multiple PDEs is necessary to increase intracellular cAMP and the PDE-regulated phosphoproteome.…”