Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Gorja, Dhilli Rao; Mukherjee, Somenath; Meda, Chandana Lakshmi T.; Deora, Girdhar Singh; Kumar, K. Lalith; Jain, Ankit; Chaudhari, Girish Hari; Chennubhotla, Keerthana Sarma; Banote, Rakesh Kumar; Kulkarni, Pushkar; Parsa, Kishore V. L.; Mukkanti, K.; Pal, Manojit

doi:10.1039/c3ob27424a

Cited by 29 publications

(20 citation statements)

References 27 publications

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“…Roflumilast was used in 2012 for treating COPD due to its PDE‐4 inhibition activity but its therapeutic potential was limited due to its side effects such as headache, weight loss, and gastrointestinal disturbance . It is rapidly oxidized to its active metabolite, roflumilast N‐oxide, which is 2–3‐fold less specific and potent than roflumilast .…”

Section: Introductionmentioning

confidence: 99%

“…9 Roflumilast was used in 2012 for treating COPD due to its PDE-4 inhibition activity but its therapeutic potential was limited due to its side effects such as headache, weight loss, and gastrointestinal disturbance. [10][11][12] It is rapidly oxidized to its active metabolite, roflumilast N-oxide, which is 2-3-fold less specific and potent than roflumilast. 13 Inter-individual variability is predicted to affect the pharmacokinetics of roflumilast as a result of its effect on the activity of the metabolizing enzymes.…”

Section: Introductionmentioning

confidence: 99%

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Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

Moussa

El‐Zaher

El-Ashrey

et al. 2019

Drug Testing and Analysis

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With the aim of studying their in vitro and in vivo pharmacokinetics, new chromatographic methods were developed for the determination of three new roflumilast synthetic analogs (I−III) as PDE‐4B inhibitors in rat liver S9 fraction, phosphate buffered saline, pH 7.4, and human and rat plasma. The developed high performance liquid chromatography−ultra violet (HPLC−UV) methods were performed on a Zorbax Eclipse C8 column and UV detection was carried out at 215 nm. The three compounds were tested for their metabolic stability and were found to be metabolically more stable than roflumilast especially the 2‐mercaptobenzothiazol‐6‐yl analog (III) which displayed an in vitro half‐life time (247.55 minutes) higher than that of roflumilast (12.29 minutes) and a low in vitro clearance of 5.67 mL/min./kg. Possible phase I metabolites were investigated using ultra‐performance liquid chromatography−tandem mass spectrometry (UPLC–MS/MS) showing hydroxylation of the unsubstituted benzothiazol‐2‐yl (I) and benzothiazole‐6‐yl (II) analogs and a cleaved benzothiazole metabolite of the 2‐mercaptobenzothiazol‐6‐yl analog (III). Plasma protein binding affinity was tested using equilibrium membrane dialysis method showing a very high percentage (more than 95%) of plasma protein binding of compounds I and II where compound III exhibited lower percentage (53.71%) demonstrating its accessibility for tissue distribution. Also, a UPLC–MS/MS method was developed using an Acquity UPLC BEH shield RP C18 column to be applied to an in vivo pharmacokinetic study in rats following a subcutaneous dose (1 mg/kg). Compounds I−III showed improved in vivo pharmacokinetic parameters especially compound III which displayed a half‐life 3‐fold greater than roflumilast (21 hours) and a Cmax value of 113.958 ng/mL. Accordingly, this new chemical entity should be subjected to further investigation as it can be a good drug candidate for treating chronic obstructive pulmonary disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

Moussa

El‐Zaher

El-Ashrey

et al. 2019

Drug Testing and Analysis

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“…Thus, selective inhibition of PDE4B was thought to provide a means to achieve efficacy while mitigating the adverse effects of the current PDE4 inhibitors. However, in spite of innumerable efforts, only a few PDE4B selective inhibitors have been reported till date …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors

Almatary

Elmorsy

Husseiny

et al. 2018

Archiv der Pharmazie

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A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner.

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“…The compounds were tested for their enzyme inhibition activity against α-amylase by the previously reported method (Gorja et al, 2013). For assay 5 µL of each test compound with the final concentration of 200, 100 and 50 µg/mL was mixed with 40 µL of starch (0.05%) and 30 µL of potassium phosphate buffer (pH 6.8) in 96-well micro titer plates followed by the addition of 10 µL of α-amylase enzyme (0.2 U/well).…”

Section: α-Amylase Assaymentioning

confidence: 99%

New 1-octanoyl-3-aryl thiourea derivatives: Solvent-free synthesis, characterization and multi-target biological activities

Larik

Saeed

Channar

et al. 2016

Bangladesh J Pharmacol

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An efficient solvent-free synthesis of a 10-member library of octanoyl linked substituted aryl thioureas was accomplished successfully. The octanoyl isothiocyanate was freshly prepared in excellent yield and purity by the reaction of potassium thiocyanate with octanoyl chloride followed by removal of potassium chloride by filtration. The reaction of the latter with a series of ten different substituted anilines by stirring at 60-65°C lead to the formation of the title compounds. The in vitro antifungal activity of newly synthesized compounds was evaluated against Aspergillus niger, A. flavus and Fusarium solani strains of pathogenic fungi. Antibacterial assay was carried out against Gram positive (Staphylococcus aureus, Micrococcus luteus) and Gram negative bacterial strains (Escherichia coli, Enterobacter aerogens). Furthermore, anti-oxidant potential and enzyme inhibition studies against α-amylase and butyryl cholinestrase were performed. The results obtained indicated moderate to excellent activities of most of the compounds whilst some derivatives showed potency higher than the standard used.Video Clips:<a href="https://www.youtube.com/v/GJ8JFPUHdo4">Antibacterial assay</a>: 2 min 16 sec<a href="https://www.youtube.com/v/1j73_wjZaOE">Enzyme inhibition</a>: 1 min 27 sec

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Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Cited by 29 publications

References 27 publications

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

Design, synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors

New 1-octanoyl-3-aryl thiourea derivatives: Solvent-free synthesis, characterization and multi-target biological activities

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