Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists

Istvan Ledneczki, P. Tapolcsányi, Eszter Gábor, János Éles, István Greiner, Éva Schmidt, Zsolt Némethy, Rita Soukupné Kedves, Ottilia Balázs, Viktor Román, György Lévay, Sándor Mahó

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3 Citations (Scopus)

Abstract

Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.

Original languageEnglish
Pages (from-to)4525-4530
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number19
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • Antagonist/inverse agonist
  • Dipsogenia model
  • Estrane derivatives
  • Histamine H receptor
  • Steroid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Ledneczki, I., Tapolcsányi, P., Gábor, E., Éles, J., Greiner, I., Schmidt, É., Némethy, Z., Kedves, R. S., Balázs, O., Román, V., Lévay, G., & Mahó, S. (2017). Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Bioorganic and Medicinal Chemistry Letters, 27(19), 4525-4530. https://doi.org/10.1016/j.bmcl.2017.08.060