2. Academic Validation
  3. Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile

Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile

  • ACS Chem Neurosci. 2024 Dec 18;15(24):4441-4457. doi: 10.1021/acschemneuro.4c00480.
Tadeusz Karcz 1,  Katarzyna Szczepańska 2,  Szczepan Mogilski 3,  Aleksandra Moroz 4,  Agnieszka Olejarz-Maciej 1,  Laura J Humphrys 5,  Steffen Pockes 5,  Agata Siwek 6,  Krzysztof Dubiel 4,  Marek Staszewski 7,  Thierry Calmels 8,  Krzysztof Waczyński 7,  Katarzyna Kieć-Kononowicz 1
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 2 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
  • 3 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 4 R&D Centre, Celon Pharma S.A., Marymoncka 15, Kazuń Nowy 05-152, Poland.
  • 5 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, Regensburg D-93053, Germany.
  • 6 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 7 Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszyńskiego 1, Łódź 90-151, Poland.
  • 8 Bioprojet-Biotech, 4rue du Chesnay Beauregard, Saint-Gregoire Cedex 35762, France.
PMID: 39652796 DOI: 10.1021/acschemneuro.4c00480
Abstract

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H3 and H4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M1, M2, and M4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.

Keywords

ADMETox properties; functional characterization; guanidines; histamine H3 receptor; multi-target directed ligand; muscarinic receptors; pain.

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