Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Huang, Chang; Zhong, Qiuping; Tang, Lv; Wang, Haitao; Zhou, Zhong‐Zhen

doi:10.1111/cbdd.13438

Cited by 8 publications

(2 citation statements)

References 60 publications

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“…Our previous study discovered some PDE4 inhibitors ,− with enhancing memory or improving depression-like behavior. Among these compounds, FCPR03 , and FCPR16 displayed antidepressant-like effects and neuroprotection without emesis at effective doses.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments

Xia

Feng

et al. 2022

ACS Chem. Neurosci.

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To realize PDE4 inhibitors with good developmental potentiality for the treatment of dementia, structure-based optimizations of lead compound FCPR03 resulted in novel aminophenylketones 9c and 9H with low nanomolar potency, which displayed comparable activity to rolipram, satisfactory bioavailability (F% = 36.92 and 42.96% respectively), and good blood–brain barrier (BBB) permeability switching from the cyclopropyl methoxy group to the cyclopropyl methylamine and the amide group to the corresponding ketone. Emetogenicity evaluation on a combined ketamine/xylazine anesthesia mice alternative model demonstrated that 9H displays no emetogenicity even at an oral dose of 5 mg/kg. In contrast, rolipram and roflumilast displayed emetogenicity at an oral dose of 0.5 mg/kg. In acute toxicological evaluation, 9H showed no obvious toxicological effect on mice when administered at oral doses below 625 mg/kg. Further investigations revealed that 9H improves the memory and cognitive impairment of Alzheimer’s disease (AD) model mice induced by Aβ25–35.

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Section: Introductionmentioning

confidence: 99%

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments

Xia

Feng

et al. 2022

ACS Chem. Neurosci.

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“…QSAR modelling is also attractive for lead optimisation through the identification of areas responsible for biological activity. A 3D-QSAR model was utilised for the lead optimisation of phosphodiesterase 4 (PDE4) inhibitors that could be used for major depressive disorder [ 25 ]. Previous leads were optimised by the addition of hydrophobic and hydrogen bonding groups that extended into other pockets of the active site.…”

Section: Ligand Based Techniquesmentioning

confidence: 99%

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

2023

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Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is complicated by the high failure rate in late-stage clinical trials, resulting in exorbitant costs associated with bringing new CNS drugs to market. Computer-aided drug design (CADD) techniques minimise the time and cost burdens associated with drug research and development by ensuring an advantageous starting point for pre-clinical and clinical assessments. The key elements of CADD are divided into ligand-based and structure-based methods. Ligand-based methods encompass techniques including pharmacophore modelling and quantitative structure activity relationships (QSARs), which use the relationship between biological activity and chemical structure to ascertain suitable lead molecules. In contrast, structure-based methods use information about the binding site architecture from an established protein structure to select suitable molecules for further investigation. In recent years, deep learning techniques have been applied in drug design and present an exciting addition to CADD workflows. Despite the difficulties associated with CNS drug discovery, advances towards new pharmaceutical treatments continue to be made, and CADD has supported these findings. This review explores various CADD techniques and discusses applications in CNS drug discovery from 2018 to November 2022.

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The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure

Nadur

Azevedo

Caruso

et al. 2021

European Journal of Medicinal Chemistry

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Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Cited by 8 publications

References 60 publications

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure

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