Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

Bartolomé-Nebreda, José Manuel; Diego, Sergio A. Alonso de; Artola, Marta; Delgado, Francisco; Delgado, Oscar; Martín-Martín, María Luz; Martínez-Viturro, Carlos M.; Pena, Miguel Ángel; Tong, Han Min; Gool, Michiel Van; Alonso, J.M.; Fontana, Alberto; Macdonald, Gregor; Megens, Anton; Langlois, Xavier; Somers, Marijke; Vanhoof, Greet; Conde-Ceide, Susana

doi:10.1021/jm501651a

Cited by 18 publications

(5 citation statements)

References 26 publications

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“…Preliminary mechanistic investigations were conducted via four control experiments (Scheme 4 ). Treatment of 1a (0.10 mmol) with LiI ( 2a ) (0.10 mmol)/Selectfluor ( 3 ) (0.10 mmol) in DMF at 15 °C gave 6a 21 in 90% yield (Scheme 4 , eq 1). The trifluoromethylation of 6a (0.10 mmol) with FSO 2 CF 2 CO 2 Me ( 4 ) (0.30 mmol) in DMF with the assistance of CuI (15 mmol%) at 100 °C produced 5a in 80% yield (Scheme 4 , eq 2).…”

Section: Table 1 Screening the Reaction Conditions ...mentioning

confidence: 99%

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

Hu¹,

Li²,

Shi³

et al. 2022

Synthesis

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The synthesis of 5-trifluoromethyl-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides via the iodination of 2-aminopyrazines with Selectfluor/LiI followed by a domino trifluoromethylation with FSO2CF2CO2Me and a condensation with DMF in the presence of CuI is realized under mild conditions. This three-step method offers CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides in yields of 55–70% and with high regioselectivities. LiI serves as an iodine source, whilst DMF functions as both a solvent and a condensation reagent. The regioselectivity of these trifluoromethylation reactions is strongly dependent upon the substituent pattern on the 2-aminopyrazines. A possible mechanism for this method is also discussed.

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Section: Table 1 Screening the Reaction Conditions ...mentioning

confidence: 99%

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

Hu¹,

Li²,

Shi³

et al. 2022

Synthesis

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show abstract

“…2 ). 17 Thus, following hydroetherification, facile deprotection could provide straightforward access to β-aryl alcohols with complete regiocontrol. We herein report the discovery of an unconventional nucleophilic water surrogate that enables anti-Markovnikov hydration of styrene derivatives.…”

Section: Introductionmentioning

confidence: 99%

A base-catalyzed approach for the anti-Markovnikov hydration of styrene derivatives

Pajk

Sujansky

et al. 2022

Chem. Sci.

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“…PDE10A has been demonstrated to be a potential target for the treatment of central nervous system (CNS) disorders (3,4). Previous studies have confirmed that PDE10A inhibitors have important biological activity in the treatment of psychosis (5)(6)(7). Therefore, screening for PDE10A inhibitors is an effective strategy for the treatment of CNS disorders.…”

Section: Introductionmentioning

confidence: 99%

The rational search for PDE10A inhibitors from Sophoraï¿½flavescens roots using pharmacophore‑ and docking‑based virtual screening

et al. 2017

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Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well‑known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors. In addition, molecular docking was used to calculate the binding affinity of ligand‑PDE10A interactions and to investigate the possible binding pattern. Virtual screening based on the pharmacophore model and molecular docking was performed to identify potential PDE10A inhibitors from S. flavescens. The results demonstrated that nine hits from S. flavescens were potential PDE10A inhibitors, and their biological activity was further validated using literature mining. A total of two compounds were reported to inhibit cyclic adenosine monophosphate phosphodiesterase, and one protected against glutamate‑induced oxidative stress in the CNS. The remaining six compounds require further bioactivity validation. The results of the present study demonstrated that this method was a time‑ and cost‑saving strategy for the identification of bioactive compounds from traditional Chinese medicine.

show abstract

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

Cited by 18 publications

References 26 publications

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

A base-catalyzed approach for the anti-Markovnikov hydration of styrene derivatives

The rational search for PDE10A inhibitors from Sophoraï¿½flavescens roots using pharmacophore‑ and docking‑based virtual screening

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