Discovery of a Novel Series of Pyrazolo[1,5-<i>a</i>]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from <i>N</i>-((1<i>S</i>)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-<i>b</i>]pyrazine-4(1<i>H</i>)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders

Abstract

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.Key words phospodiesterase 2A; schizophrenia; pyrazolo[1,5-a]pyrimidine; structure-based drug design; phototoxicity; intramolecular hydrogen bond Schizophrenia is a chronic, severe, and disabling mental disorder affecting approximately 1% of the general population worldwide, [1][2][3][4] resulting in profound disruption in emotion and cognition, which has a major impact on patients' and caregivers' lives. The symptoms can typically be divided into three domains: positive (delusions and hallucinations), negative (lack of motivation and social withdrawal), and cognitive (memory, attention, and executive function) symptoms. The most recent medications commonly prescribed for schizophrenia include a new generation of antipsychotics called atypical or second-generation antipsychotics (SGAs), which function via inhibition of dopamine D2 and serotonin 5-HT 2A receptors. 5)It has been reported that these agents are reasonably effective at treating the positive symptoms of schizophrenia, but show little or no efficacy against negative and cognitive symptoms of the disease. 6) Furthermore, although generally more effective and better tolerated than typical or first-generation antipsychotics (FGAs), atypical antipsychotics also cause a variety of drug-related side effects such as sedation, weight gain, an increased risk of type II diabetes and high cholesterol, extrapyramidal symptoms, hypotension, and prolactin elevation. [7][8][9] Thus, there is a clear and high unmet medical need for a novel antipsychotic with improved efficacy and superior safety profile for the treatment of schizophrenia, especially against negative and cognitive symptoms of the disease.Owing to a growing body of preclinical research, phosphodiesterase (PDE) 2A has been recently receiving significant attention for its therapeutic potential to ...

Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat

“…]cyclohepten-5,10-imine-induced episodic memory deficits at oral doses of 3 and 10 mg/kg (but not 1 mg/kg), which corresponded well with the dose that elevated hippocampal cGMP levels, where occupancy was reported to be about 46% and 63% at these doses, respectively (Mikami et al, 2017a). However, N-((1S)-1-(3fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide significantly enhanced performance in the rat novel object recognition study (Mikami et al, 2017b) at a dose of 0.1 mg/kg, presumably at occupancy far lower than 46%.…”

“…In evaluating PDE2A target occupancy by PDE2A inhibitors, the positive cooperativity of the enzyme should be considered. Since the doses of the PDE2A inhibitor required to reverse chemical-challenged cognitive deficits were relatively high (Mikami et al, 2017a;Helal et al, 2018), this positive cooperativity might have been masked. In the current study, we used a nonchemically challenged long-term memory retention model and in vivo autoradiography to investigate the target engagement of a potent and selective PDE2A inhibitor, PF-05180999, at the low efficacious doses.…”

A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome

“…5 Many studies have supported the use of PDE2A inhibitors as a potential treatment for cognitive disorders, working memory, and executive function. 6 PDE2A was also recently shown to play a role in the physiopathology of fragile X mental retardation syndrome (FXS), and its pharmacological inhibition was proposed as a potential therapeutic approach for FXS. 7 This suggests that PDE2A gain of function would lead to intellectual disability (ID).…”

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

“…Selective bromination of 3 with N-bromosuccinimide in dichloromethane afforded the bromo derivative 4 in 94% yield. The 3-bromo-7-(trifluoromethyl) pyrazolo [1,5-a]pyrimidin-5-one 4 served as a building block for the synthesis of 3,5-disubstituted 7-(trifluoromethyl)pyrazolo [1,5-a] a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively. The incorporation of a fluorine atom into potential pharmaceutical substances has been successfully used as a key strategy for enhancing the activity of drugs or drug candidates [27,28].…”

“…Moreover, pyrazolo [1,5-a]pyrimidines are also known as antagonists of serotonin 5-HT6 receptors [15], and also act as inhibitors of histone lysine demethylase 4D (KDM4D) [16] as well as several kinases such as Pim kinase [17,18], threonine tyrosine kinase (TTK) [19], and cyclin-dependent kinases (CDKs) [20]. In addition, some pyrazolo [1,5-a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively.…”