Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement

Buijnsters, Peter; Angelis, Meri De; Langlois, Xavier; Rombouts, Frederik; Sanderson, Wendy; Tresadern, Gary; Ritchie, Alison; Trabanco, Andrés A.; Vanhoof, Greet; Roosbroeck, Yves Van; Andrés, José-Ignacio

doi:10.1021/ml500262u

Cited by 43 publications

(56 citation statements)

References 17 publications

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“…8). Consistent with the previous observations, 11,29,42,43,50) compound 20 dose-dependently increased cGMP levels in all selected brain regions at doses as low as 3 mg/kg, corresponding to ca. 37% occupancy levels, while not affecting cAMP levels.…”

Section: Resultssupporting

confidence: 91%

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

Mikami

Kawasaki

Ikeda

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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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 ...

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Section: Resultssupporting

confidence: 91%

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

Mikami

Kawasaki

Ikeda

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…In particular the combination of the previously exemplified 1-aryl-4-methyl-[1,2,4]-triazolo[4,3-a]quinoxaline compounds with MP-10, 62 PQ-10, 67 TP-10,68 papaverine,69 and PDE10A inhibitors disclosed in two other Janssen patents is claimed 70,71. Janssen also reported the discovery of 42 and 44 following optimization of the HTS hit 47 in two publications (Figure 12) 72,73. While selectivity of 42 versus PDE10A was moderate (~10-fold), excellent PDE2A selectivity (> 600-fold) was reported over the 1, 3, 4, 5, 6, 7, 9 and 11 PDE isoforms.…”

mentioning

confidence: 94%

Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present)

Trabanco

Buijnsters

Rombouts

2016

Expert Opinion on Therapeutic Patents

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Recent publications in the literature and in filed patent applications demonstrate the interest of pharmaceutical companies for PDE2A. This has increased the insights of its possible therapeutic role but the few clinical trials were terminated. Based on the ongoing interest in the field it is likely that new clinical trials can be expected and will unravel the therapeutic potential of PDE2A inhibition.

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“…non-homologous) proteins allow a compound to bind to these different proteins [10]. This also holds true for similarities in the non-covalent interaction patterns [6]. The inhibitor forms characteristic, non-covalent protein-ligand interactions [9] that can be exploited to discover new small molecules with diverse scaffolds.…”

Section: Computational Drug Discoverymentioning

confidence: 99%

“…PDE2 hydrolyzes cAMP and cGMP, with its dual-specificity being determined by a freely rotating glutamine residue [4]. PDE2 plays an important role in growth and invasion of melanoma cells [5] and the development of specific inhibitors of PDE2 is an ongoing field of research [6,7]. The selective inhibition of PDE2 was linked, for example, to improved object memory and synaptic plasticity [8].…”

Section: Introductionmentioning

confidence: 99%

Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors within silicoDriven Library Prioritization and MicroScale Thermophoresis

Kaiser¹,

Plach²,

Schubert³

et al. 2020

Preprint

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Accelerated development of lead structures is of high interest to the pharmaceutical industry in order to decrease development times and costs. We showcase how an intelligent combination of AI-based drug screening with stateof-the-art biophysics drives the rapid identification of novel inhibitor structures with high chemical diversity for cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2). The starting point was an off-the-shelve chemical library of two million drug-like compounds. In a single in silico reduction step, we short-listed 125 compounds -the focused library -as potential binders to PDE2 and tested their binding behavior in vitro using MicroScale Thermophoresis (MST). Of this focused library, seven compounds indicated binding to PDE2, translating to a hit rate of 6%. Three of these compounds have affinities in the lower micromolar range. The compound with the highest affinity showed a K D of 10 µM and is thus an excellent starting point for further medicinal chemistry optimization. The results show how innovative and structure-driven in silico approaches and biophysics can be used to accelerate drug discovery and to obtain new molecular scaffolds at a fraction of the costs and time -compared with standard high-throughput screening.

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Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement

Cited by 43 publications

References 17 publications

Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present)

Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors within silicoDriven Library Prioritization and MicroScale Thermophoresis

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