Structure−Brain Exposure Relationships

Hitchcock, Stephen A.; Pennington, Lewis D.

doi:10.1021/jm060642i

Cited by 606 publications

(341 citation statements)

References 122 publications

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“…In addition, the compound demonstrated reasonable brain uptake with a brain to plasma ratio of 0.32 in rat, although it had a high TPSA value ( 114 2 ) outside the traditional range of CNS drugs. 44,45,49) These results suggested that the intramolecular hydrogen bonds observed in 20 effectively shield the polarity of the molecule, thus improving blood-brain barrier permeability.…”

Section: Resultsmentioning

confidence: 86%

“…Despite the fact that compounds 2 and 3 possess a nearly identical topological polar surface area (TPSA), the former has a superior MDR1 efflux ratio, indicating that the hydrogen bond donor (HBD) count (two HBDs in 2 vs. three HBDs in 3) may play a crucial role in defining each compound as a P-gp substrate. 44,45) We therefore reasoned that replacing the 3,4-dihydropyrido [2,3-b] pyrazin-2(1H)-one core in 3 with the pyrazolo[1,5-a]-pyrimidine core derived from 4 would serve to improve brain penetration by reducing the overall HBD count. Indeed, hybrid compound 5 showed reasonable inhibition of PDE2A with an IC 50 of 66 nM and no indication of being a P-gp substrate.…”

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

“…The compound exhibited improved potency and PDE selectivity with no appreciable in vitro phototoxicity potential, but was found to be susceptible to P-gp mediated efflux, most likely due to the polar or basic nitrogen atom of the imidazole ring. 44,45) In order to attenuate the basicity of the imidazole ring in 15, a two-pronged approach was implemented: first, the methyl group on the imidazole ring was replaced with an electron-withdrawing trifluoromethyl group to give 16, and second, an additional nitrogen atom was incorporated into the imidazole ring to afford two isomeric triazoles 17 and 18. As anticipated, all modifications improved the P-gp efflux ratio, and maintained favorable clearance and in vitro phototoxicity profile, although the result of the phototoxicity In an attempt to rescue insufficient potency and PDE selectivity of compounds 17 and 18, which were otherwise close to meeting our goals, the methyl substitution at the 6-position of the pyrazolo[1,5-a] pyrimidine core was examined (19, 20 in Table 2), since the 6-methyl substitution was previously shown to significantly enhance both potency and PDE selectivity.…”

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

“…Aminopyrazole 43 was initially constructed in a two-step sequence of reactions, involving the condensation of tert-butyl 2-cyanoacetate (40) and tertbutoxy bis(dimethylamino) methane (41), followed by reaction with hydrazine. The aminopyrazole 43 was then condensed with 1,3-dicarbonyl related electrophile 46 prepared by bromination of methyl methacrylate (44), prior to treatment with a methanol solution of sodium methoxide to provide pyrazolo[1,5-a] pyrimidine core 47. Regioselective installation of triazole rings at the 5-position of the core was carried out by two different approaches using conditions mild enough to be compatible with the acid-labile tert-butyl ester moiety.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

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: Resultsmentioning

confidence: 86%

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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“…In particular, PSA is commonly used to indicate whether a CNS drug can penetrate the cell membrane through passive diffusion. The PSA of a CNS drug is required to be < 90 angstroms to penetrate the blood brain barrier [39]. The numbers of filtered hit molecules were 48,379 for APRRR215 and 6,823 for AHPRRR104, with 5,770 compounds in common.…”

Section: Identification Of Cns-like D3r Antagonist Through Virtual Scmentioning

confidence: 99%

Discovery of CNS-Like D3R- Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening

Lee

Cho²,

Kim

2018

Preprint

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The dopamine D3 receptor is an important CNS target for the treatment of a variety of neurological diseases. Selective dopamine D3 receptor antagonists modulate the improvement of psychostimulant addiction and relapse. In this study, five and six featured pharmacophore models of D3R antagonists were generated and evaluated with the post-hoc score combining two survival scores of active and inactive. Among Top 10 models, APRRR215 and AHPRRR104 were chosen based on the coefficient of determination (APRRR215: R 2 training = 0.80; AHPRRR104: R 2 training = 0.82) and predictability (APRRR215: Q 2 test = 0.73, R 2 predictive = 0.82; AHPRRR104: Q 2 test = 0.86, R 2 predictive = 0.74) of their 3D-quantitative structure-activity relationship models. Pharmacophore-based virtual screening of a large compound library from eMolecules (> 3 million compounds) using two optimal models expedited the search process 100-fold speed increase compared to the docking-based screening (HTVS scoring function in Glide) and identified a series of hit compounds having promising novel scaffolds. After the screening, docking scores, as an adjuvant predictor, were added to two fitness scores (from the pharmacophore models) and predicted Ki (from PLSs of the QSAR models) to improve accuracy. Final selection of the most promising hit compounds were also evaluated for CNSlike properties as well as expected D3R antagonism.

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CNSCancers

Graeme

2010

Burger's Medicinal Chemistry and Drug Discovery

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CNS tumors represent a diverse collection of tumor types driven by a range of signaling inputs that often generate highly aggressive and at the same time heterogeneous tumor types. The effect of these tumors is particularly dramatic and impacts on children as well as adults. Malignant CNS tumors are characterized by being highly heterogeneous, aggressive, and frequently invasive, leading to poor overall patient survival times. As CNS tumors present within the nervous system, there are particular challenges in the development of effective molecular‐targeted therapies in dealing not only with the aggressive nature of these tumors and their ability to evade treatment but also, particularly, with maintaining normal neuronal and brain functions. Compounding this is the need to deliver systemically small molecules or other agents such as vaccines and for immunotherapy approaches to confront the complexity of the relationship between the nervous system and the immune system. Research to find effective treatments for CNS tumors is being facilitated by two key inputs both of which are reviewed in this chapter; first, a much greater understanding of tumor pathobiology and the potential role of developmental signaling pathways and tumor stem‐like cells, and by the development of animal models that more adequately represent endpoints measurable in the clinic. Together, these advances should assist in the selection of better targets and the optimization of better compounds to progress into clinical trials.

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Structure−Brain Exposure Relationships

Cited by 606 publications

References 122 publications

Discovery of CNS-Like D3R- Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening

CNSCancers

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