Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones

Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Ando, Nobutoshi; Iwase, Kazuhiko; Kishi, Tohru; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David H.; Kohno, Yasushi

doi:10.1016/j.bmcl.2012.07.088

Cited by 25 publications

(12 citation statements)

References 27 publications

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“…Further, smaller standard deviation value (SD = 0.56) and root mean square error (RMSE = 0.69) and P value of fourth PLS indicate that the developed AAHPRR.15 model was stable for predicting unknown compounds in the test set. To evaluate the efficacy, model AAHPRR.15 was further validated with the external 27 test set 46 , 47 . The scatter plots for the experimentally observed and estimated fit values for the training set and the test set molecules is plotted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

Jang

Yadav

Subedi

et al. 2018

Sci Rep

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In this study, pharmacophore based 3D QSAR models for human acetylcholinesterase (AChE) inhibitors were generated, with good significance, statistical values (r2training = 0.73) and predictability (q2training = 0.67). It was further validated by three methods (Fischer’s test, decoy set and Güner-Henry scoring method) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective AChE inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective AChE inhibitor. Thus, the findings reported herein may provide a new strategy for the discovery of selective AChE inhibitors. The IC50 value of compounds 5c and 6a presented selective inhibition of AChE without inhibiting butyrylcholinesterase (BChE) at uM level. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds studies to explain high affinity.

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Section: Resultsmentioning

confidence: 99%

Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

Jang

Yadav

Subedi

et al. 2018

Sci Rep

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“…With the thorough understand of inflammatory reactions, using single mice or rat model to evaluate the analgesic effect gradually fall short of demand to investigate the activity, more and more targets are involved into the determination including COX-1, COX-2, 5-LOX, TNF-a, etc. Pyrazolones with anti-inflammatory effects tend to inhibited the activities of COXs and LOXs, which catalyze the conversion of arachidonic acid into prostaglandins or leukotrienes, meanwhile, phosphatase inhibitory of pyrazolones have also been disclosed [87], indicating the potential of pyrazolone motif in this field. The structural similarity between pyrazolone and COX-2 selective inhibitor celecoxib also provides possibility to develop them into potential clinical candidates [88e91].…”

Section: Anti-inflammatory Agentsmentioning

confidence: 99%

“…Ochiai et al [87] synthesized several 4,4-dimethylpyrazolone analogues as cyclic 30,50-nucleotide PDE 3/4-inhibitor, in which the compound 179 ( Fig. 19) was demonstrated to be the most potent compound inhibiting PDE 3A and PDE 4B with the IC 50 values of 0.14 and 0.15 mM, respectively.…”

Section: Protein Inhibitorsmentioning

confidence: 99%

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Zhao

Dai

et al. 2020

European Journal of Medicinal Chemistry

151

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a b s t r a c tThe pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

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“…We commenced our investigations by targeting an expedient procedure for the synthesis of target compounds phenyl‐pyrazolo[1,5‐ a ]pyridine derivatives 4 ( a–k ) and substituted coumarin‐pyrazolo[1,5‐ a ]pyridine derivatives 7 ( a–e ), synthetic route outlined in Schemes and respectively . The derived substituted pyrazolo[1,5‐ a ]pyridine derivatives 4/7 were synthesized in one step by the reaction of 5 ‐ amino‐4‐cyano‐3‐cyanomethylpyrazole ( 1 ) with substituted aryl aldehydes ( 2 )/substituted 4‐formyl coumarins ( 5 ) and malononitrilein the presence of catalytic amount of DMAP.…”

Section: Resultsmentioning

confidence: 99%

“…Pyrazolopyridine ring structures are the constructional structure in anticancer research and drug discovery, therefore we thought of designing the molecule using pyrazole nucleus to give a fused pyrazolo[1,5‐ a ]pyridine derivatives. This synthetic approaches allowed us in the identification of the title compounds with substituted phenyls and coumarins across the ring of pyrazolo[1,5‐ a ]pyridine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Polyfunctionalized Fused Pyrazolo‐Pyridines: Characterization, Anticancer Activity, Protein Binding and Molecular Docking Studies

Naik

Shastri

et al. 2019

ChemistrySelect

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The reaction of a multi-substituted pyrazole 1 with aryl or heteroaryl aldehydes and active methylene compounds afford unexpected pyrazolo[1,5-a]pyridine derivatives 4(a-k). Mechanism for this unexpected reaction involving reactivity of the active methylene moiety with a neighboring endocyclic NH group is proposed and structure has been established by the NMR and single crystal X-ray diffraction studies. Moreover, all the newly synthesized compounds were tested for their anticancer activity against sixty human cell lines at NCI. Among all the compounds, three scaffolds 4d, 4 h and 4k showed enhancement in anticancer activity in comparison with remaining synthesized compounds. Interestingly compound 4k was found to highly active even at a five dose concentration. The IC 50 values were determined against two cell lines MCF-7 and HepG2, the results obtained have shown promising effects against cancer cell lines. Further, the molecular docking studies revealed that substituted pyrazolo[1,5-a]pyridine derivatives are good candidates in the medicinal field.

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Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones

Cited by 25 publications

References 27 publications

Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Synthesis of Polyfunctionalized Fused Pyrazolo‐Pyridines: Characterization, Anticancer Activity, Protein Binding and Molecular Docking Studies

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