Synthesis of Substituted 3‐Anilino‐5‐phenyl‐1,3‐dihydro‐ 2<i>H</i>‐1,4‐benzodiazepine‐2‐ones and their Evaluation as Cholecystokinin‐Ligands

Offel, Michael; Lattmann, Pornthip; Singh, Harjit; Billington, David C.; Bunprakob, Yodchai; Sattayasai, Jintana; Lattmann, Eric

doi:10.1002/ardp.200500217

Cited by 15 publications

(11 citation statements)

References 30 publications

(22 reference statements)

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“…The most potent antagonists 31a-d displayed affinities of 11, 10, 11 and 9 nM, respectively, at this receptor subtype and (320-545)-fold selectivity over the CCK2R. Furthermore, 31a-d exhibited an antidepressant effect in mice in the tail suspension-and the Porsolt swimming-tests [61]. The N-Me derivative 31e was a mixed CCK1R/CCK2R antagonist, which showed antidepressant and anxiolytic properties.…”

Section: 4-benzodiazepine Derivativesmentioning

confidence: 98%

“…With the main goal of improving water solubility of 3-ureido-1,4-benzodiazepine-based CCK antagonists, researchers at the Aston University have recently patented [60] and reported [61] a series of racemic 3-anilino-7-chloro-5-phenyl-1,3-dihydro-2-H-1,4-benzodiazepines of general formula 31, where the protonable amino group replaces the 3-ureido group of known CCK2R antagonists. The binding affinities of these benzodiazepine derivatives at CCK1R and CCK2R were determined in rat pancreas (CCK1R) and guinea pig cerebral cortex (CCK2R) homogenates.…”

Section: 4-benzodiazepine Derivativesmentioning

confidence: 99%

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Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

García-López¹,

González‐Muñiz²,

Martı́n-Martı́nez³

et al. 2007

CTMC

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This review mainly covers last five year literature on CCK1R agonists and antagonists. These CCK1R ligands have been found following the two usual and complementary strategies for drug discovery: rational design based on structure activity relationships on the CCK-7 and CCK-4 peptide sequences of the endogenous ligands and random screening of diverse compounds, followed by hit optimization. The first group includes: chimeric bifunctional opioid/CCK peptides, designed as opioid agonists with balanced CCK1R/CCK2R antagonist activity for the treatment of neuropathic pain, antagonist and agonist dipeptoids, and 1,3-dioxoperhydropyrido[1,2-c]pyrimidine- and anthranilic acid-based antagonists. Among the ligands derived from random screening, a few new 1,4-benzodiazepine-, 1,5-benzodiazepine-, and five member ring heterocycle-based CCK1R ligands have been reported. Finally, taking into account the importance of receptor mapping studies for ligand optimization and future precise de novo receptor structure-based design of new selective and more effective ligands, the most significant conclusions of these studies have also been reviewed.

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Section: 4-benzodiazepine Derivativesmentioning

confidence: 98%

Section: 4-benzodiazepine Derivativesmentioning

confidence: 99%

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

García-López¹,

González‐Muñiz²,

Martı́n-Martı́nez³

et al. 2007

CTMC

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“…[19]. Alternatively,oxazepamwasr eacted according torouteB [ 20]: Asynthesisof 2-dialkylamino-1,4-benzodiazepines [21]isr eported using phosphorane chemistry [22]a nd fort he detailed synthesisof oxazepamsee [23].…”

Section: Cns-activedrugsmentioning

confidence: 99%

In vivo Evaluation of Substituted 3-Amino-1,4-benzodiazepines as Anti-depressant, Anxiolytic and Anti-nociceptive Agents

Lattmann

Boonprakob

et al. 2011

Arzneimittelforschung

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Oxazepam (CAS 604-75-1) 4a served as building block in the synthesis of substituted 3-amino-1,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phosphor-oxy derivative (Method B) giving the desired 3-amino-1,4-benzodiapines 6a-6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substituted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6e showed anxiolytic and antidepressant effects from 10 microg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinociception with a maximum possible effect (MPE) about 35%. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vive evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6p displayed a similar dose-response relationship to morphine, but was 3 times more potent.

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“…Here, a full biological evaluation of the PNB-cancer molecules towards PNB-101, a potent and selective fluorinated gastrin antagonist will be reported in detail with respect to the anti-neoplastic properties of the molecule, in particular for lung cancer. [19][20][21][22][23][24][25][26][27]…”

Section: Introductionmentioning

confidence: 99%

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

Lattmann

Russell

Singh

et al. 2018

MOJDDT

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Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK 1 R and CCK2R receptors are ideal molecular targets for novel smart chemotherapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK 2 R) antagonists are ideal experimental drug candidates. Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK 2 / gastrin selective for the treatment of lung cancers. Methods: A fast and efficient synthesis of hydroxy-pyrrolones in 2 steps from renewable biomass was performed. After initial radiolabelled receptor binding studies with hot CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism. Cell based studies using the MTT assay provided a candidate for in vivo xenograft models with nude mice. Rational drug design was supported by molecular modelling experiments. Results: Potent and selective CCK antagonists were prepared as stable crystalline materials in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations and inhibited breast, colon and lung cancer cell lines in vitro with IC 50 to 45nM for the privileged hydroxyl-pyrrolone lead structure in the MTT assay for human cancer cell lines. PNB-101, a fluorinated 5-hydroxy-5-aryl-pyrrol-2-one, gave up to 80% inhibition of tumour growths by oral administration in athymic mice transplanted with the human lung cancer cell line H727. Conclusion: PNB-101 is a potential chemotherapeutic agent for CCK-gastrin related cancers and entered preclinical development.

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Synthesis of Substituted 3‐Anilino‐5‐phenyl‐1,3‐dihydro‐ 2H‐1,4‐benzodiazepine‐2‐ones and their Evaluation as Cholecystokinin‐Ligands

Cited by 15 publications

References 30 publications

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

In vivo Evaluation of Substituted 3-Amino-1,4-benzodiazepines as Anti-depressant, Anxiolytic and Anti-nociceptive Agents

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

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