Literature DB >> 29116786

Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

Olivier Bezençon1, Bibia Heidmann1, Romain Siegrist1, Simon Stamm1, Sylvia Richard1, Davide Pozzi1, Olivier Corminboeuf1, Catherine Roch1, Melanie Kessler1, Eric A Ertel1, Isabelle Reymond1, Thomas Pfeifer1, Ruben de Kanter1, Michael Toeroek-Schafroth1, Luca G Moccia1, Jacques Mawet1, Richard Moon1, Markus Rey1, Bruno Capeleto1, Elvire Fournier1.   

Abstract

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

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Year:  2017        PMID： 29116786     DOI： 10.1021/acs.jmedchem.7b01236

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  7 in total

1.  Multiple-Ascending Dose Study in Healthy Subjects to Assess the Pharmacokinetics, Tolerability, and CYP3A4 Interaction Potential of the T-Type Calcium Channel Blocker ACT-709478, A Potential New Antiepileptic Drug.

Authors:  Muriel Richard; Priska Kaufmann; Marion Ort; Rüdiger Kornberger; Jasper Dingemanse
Journal:  CNS Drugs       Date:  2020-03       Impact factor: 5.749

2.  Iron-Nickel Dual-Catalysis: A New Engine for Olefin Functionalization and the Formation of Quaternary Centers.

Authors:  Samantha A Green; Suhelen Vásquez-Céspedes; Ryan A Shenvi
Journal:  J Am Chem Soc       Date:  2018-07-26       Impact factor: 15.419

Review 3.  Put a ring on it: application of small aliphatic rings in medicinal chemistry.

Authors:  Matthias R Bauer; Paolo Di Fruscia; Simon C C Lucas; Iacovos N Michaelides; Jennifer E Nelson; R Ian Storer; Benjamin C Whitehurst
Journal:  RSC Med Chem       Date:  2021-01-07

4.  Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers.

Authors:  Ahmed M Farghaly; Ola H Rizk; Inas Darwish; Manal Hamza; Mezna Saleh Altowyan; Assem Barakat; Mohamed Teleb
Journal:  Molecules       Date:  2022-03-30       Impact factor: 4.411

Review 5.  Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets.

Authors:  Sascha R A Alles; Peter A Smith
Journal:  Front Pain Res (Lausanne)       Date:  2021-12-13

6.  Ligand-based prediction of hERG-mediated cardiotoxicity based on the integration of different machine learning techniques.

Authors:  Pietro Delre; Giovanna J Lavado; Giuseppe Lamanna; Michele Saviano; Alessandra Roncaglioni; Emilio Benfenati; Giuseppe Felice Mangiatordi; Domenico Gadaleta
Journal:  Front Pharmacol       Date:  2022-09-05       Impact factor: 5.988

7.  T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.

Authors:  Karol Granados; Laura Hüser; Aniello Federico; Sachindra Sachindra; Gretchen Wolff; Thomas Hielscher; Daniel Novak; Verónica Madrigal-Gamboa; Qian Sun; Marlene Vierthaler; Lionel Larribère; Viktor Umansky; Jochen Utikal
Journal:  Br J Cancer       Date:  2020-02-17       Impact factor: 7.640
  7 in total

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