Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition

Hamaguchi, Wataru; Masuda, Naoyuki; Miyamoto, Sadaaki; Shiina, Yasuhiro; Kikuchi, Shigetoshi; Mihara, Takuma; Moriguchi, Hiroyuki; Fushiki, Hiroaki; Murakami, Yoshihiro; Amano, Y.; Honbou, Kazuya; Hattori, Kouji

doi:10.1016/j.bmc.2014.11.039

Cited by 21 publications

(13 citation statements)

References 42 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2015, Hamaguchi et al [161] reported on the development of another series of compound 22 -related derivatives based on the quinoline analogue 41 [162] (Figure 7). Compared to 22 (MP-10), compound 41 is of reduced inhibitory potency towards PDE10A (IC 50 = 29 nM vs. 0.55 nM [161,162]), but of higher metabolic stability as shown by in vitro studies using mouse and human liver microsomes (M/HLM) [162]. Structural modification of 41 led to the most promising derivative 42 that exhibited a significantly increased PDE10A potency (IC 50 = 5.1 nM) and further enhanced in vitro stability in M/HLM studies [161].…”

Section: Pde10 Radioligandsmentioning

confidence: 99%

“…Compared to 22 (MP-10), compound 41 is of reduced inhibitory potency towards PDE10A (IC 50 = 29 nM vs. 0.55 nM [161,162]), but of higher metabolic stability as shown by in vitro studies using mouse and human liver microsomes (M/HLM) [162]. Structural modification of 41 led to the most promising derivative 42 that exhibited a significantly increased PDE10A potency (IC 50 = 5.1 nM) and further enhanced in vitro stability in M/HLM studies [161]. Thus, 42 has been selected for 11 C-labeling to evaluate this novel PDE10A inhibitor in vivo with PET (Figure 7).…”

Section: Pde10 Radioligandsmentioning

confidence: 99%

See 1 more Smart Citation

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

et al. 2016

View full text Add to dashboard Cite

Cyclic nucleotide phosphodiesterases (PDEs) are a class of intracellular enzymes that inactivate the secondary messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Thus, PDEs regulate the signaling cascades mediated by these cyclic nucleotides and affect fundamental intracellular processes. Pharmacological inhibition of PDE activity is a promising strategy for treatment of several diseases. However, the role of the different PDEs in related pathologies is not completely clarified yet. PDE-specific radioligands enable non-invasive visualization and quantification of these enzymes by positron emission tomography (PET) in vivo and provide an important translational tool for elucidation of the relationship between altered expression of PDEs and pathophysiological effects as well as (pre-)clinical evaluation of novel PDE inhibitors developed as therapeutics. Herein we present an overview of novel PDE radioligands for PET published since 2012.

show abstract

Section: Pde10 Radioligandsmentioning

confidence: 99%

Section: Pde10 Radioligandsmentioning

confidence: 99%

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Quinoline derivatives are largely used in the pharmaceutical chemistry owing to the wide range of applications. Quinoline derivatives possess various biological activities such as antiviral , anticancer , antibacterial , antifungal , anti‐obesity , anti‐inflammatory , antimalarial , antituberculosis , hypnotic , antischizophrenic , anti‐protozoal , anti‐cholesterol , anthelmintic , and analgesic activities , and these activities were demonstrated in drug molecules, which are shown in Figure . At present, a wide range of microorganism such as fungi, viruses, and bacteria are becoming resistant against drugs that are used to treat infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological andIn SilicoStudy of Fluorine‐Containing Quinoline Hybrid Thiosemicarbazide Analogues

Patel

Prajapati

et al. 2019

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

A novel series of fluorine‐containing quinoline hybrid thiosemicarbazide analogues (8a–8l) were synthesized and tested for their biological activities. The antibacterial results demonstrated that compounds 8d and 8l [minimal inhibitory concentration (MIC) 62.5 μg/mL] were shown to have higher biological activity than ampicillin against Escherichia coli. Compound 8b (MIC 25 μg/mL) was shown to have the highest activity than was ampicillin against Staphylococcus aureus. The antifungal results demonstrated that compound 8j (MIC 100 μg/mL) has shown good activity. Most of the targeted compounds have shown potent antimalarial activity. Compounds 8d (0.19 μg/mL), 8g (0.30 μg/mL), 8h (0.36 μg/mL), 8k (0.10 μg/mL), 8l (0.28 μg/mL), 8k (0.10 μg/mL), and 8l (0.28 μg/mL) have notable activity than does the reference drug quinine. Compounds 8d (0.27 μg/mL), 8g (0.30 μg/mL), and 8k (0.17 μg/mL) have shown excellent activity against chloroquine‐resistant strain. The MTT assay performed on peripheral blood lymphocyte cultures showed a high percentage of lymphocyte viability [8d (99.64), 8g (99.46), 8h (98.83), and 8k (99.51)] at a maximum dose (10 μg/mL), depicting no cytotoxicity of these compounds on human lymphocytes in vitro. A molecular docking study was performed on Pf‐DHFR‐TS inhibitor. A molecular dynamics study has shown compound 8g to have better affinity with protein. ADME‐Tox and pharmacophore study of synthesized compounds suggested prediction of active site.

show abstract

“…The authors report on the correlation of the target IC 50 with the HBA strength of the acceptor atom in a variable heterocyclic R‐group attached to a methyl‐pyrazole moiety . In the absence of a HBA prediction model they correlate the experimental values from existing fragments in the p K BHX database.…”

Section: Resultsmentioning

confidence: 99%

“…The importance of the quantification of hydrogen bonding, in molecules of interest to medicinal chemistry has continually been brought into focus by academic and industrial researchers ,,,. Recent publications deal with the impact of hydrogen bond acceptor (HBA) strengths on p‐glycoprotein and permeability, or the correlation of HBA strengths of a (hetero‐) aromatic group to the inhibitory activity for their target phosphodiesterase 10 A . Similar investigations have also been performed on multiple kinase projects .…”

Section: Introductionmentioning

confidence: 99%

Gaussian Process Regression Models for the Prediction of Hydrogen Bond Acceptor Strengths

Bauer

Schneider

Göller

2018

Molecular Informatics

View full text Add to dashboard Cite

We present two approaches for the computation of hydrogen bond acceptor strengths, one by machinelearning and one by a composite quantum-mechanical protocol, both based on the well-established pK BHX scale and dataset. The QM calculations after a necessary linear fit reproduce the complexation free energies in solution with an RMSE of 2.6 kJ mol À1 , not far off the expected error of 2 kJ mol À1 obtained from the comparison of experimental data from two different sources. The second approach is by Gaussian Process Regression (GPR) machine-learning. We describe the hydrogen bond acceptor atoms by a radial atomic reactivity descriptor that encodes their electronic and steric environment. The performance of the GPR model on an external test set corresponds to 3.3 kJ mol À1 , which is also close to the experimental error. We apply the GPR model built on experimental data to model the hydrogen bond acceptor strengths of a series of hydrogen bond acceptor sites of 10 phosphodiesterase 10 A inhibitors. The predicted values correlate well with the experimentally measured IC 50 values.Keywords: hydrogen bonds · structure-property relation · machine learning · computational chemistry · density functional theory[a] C.

show abstract

Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition

Cited by 21 publications

References 42 publications

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

Novel Radioligands for Cyclic Nucleotide Phosphodiesterase Imaging with Positron Emission Tomography: An Update on Developments Since 2012

Design, Synthesis, and Biological andIn SilicoStudy of Fluorine‐Containing Quinoline Hybrid Thiosemicarbazide Analogues

Gaussian Process Regression Models for the Prediction of Hydrogen Bond Acceptor Strengths

Contact Info

Product

Resources

About