Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives

István Ledneczki, Zsolt Némethy, P. Tapolcsányi, János Éles, István Greiner, Eszter Gábor, Balázs Varga, Ottilia Balázs, Viktor Román, György Lévay, Sándor Mahó

Research output: Contribution to journalArticle

Abstract

To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an ‘amine-to-amide’ modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.

Original languageEnglish
Article number126643
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number20
DOIs
Publication statusPublished - Oct 15 2019

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Histamine H3 Antagonists
Histamine H3 Receptors
Rats
Steroids
Derivatives
Amides
Pharmacodynamics
Muscarinic Receptors
Inner Ear
Microsomes
Amines
Water

Keywords

  • Antagonist/inverse agonist
  • Carboxamide
  • Dipsogenia test
  • Histamine H receptor
  • Steroid
  • Water-labyrinth test

ASJC Scopus subject areas

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

Cite this

Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives. / Ledneczki, István; Némethy, Zsolt; Tapolcsányi, P.; Éles, János; Greiner, István; Gábor, Eszter; Varga, Balázs; Balázs, Ottilia; Román, Viktor; Lévay, György; Mahó, Sándor.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 20, 126643, 15.10.2019.

Research output: Contribution to journalArticle

Ledneczki, István ; Némethy, Zsolt ; Tapolcsányi, P. ; Éles, János ; Greiner, István ; Gábor, Eszter ; Varga, Balázs ; Balázs, Ottilia ; Román, Viktor ; Lévay, György ; Mahó, Sándor. / Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 20.
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