2. Academic Validation
  3. Leveraging Peripheral CB1 Antagonism in 1,4,5,6-Tetrahydropyridazine-Based Amidine Substituted Sulfonyl Analogs for Treating Metabolic Disorders

Leveraging Peripheral CB1 Antagonism in 1,4,5,6-Tetrahydropyridazine-Based Amidine Substituted Sulfonyl Analogs for Treating Metabolic Disorders

  • J Med Chem. 2025 Oct 23;68(20):21224-21248. doi: 10.1021/acs.jmedchem.5c01158.
Pinaki Bhattacharjee 1,  Szabolcs Dvorácskó 1 2 3,  Paul Volesky 1,  Océane Pointeau 4,  Nicholas Rutland 1,  Luca Maccioni 5 6,  Grzegorz Godlewski 6,  Tony Jourdan 4,  Sergio A Hassan 7,  Resat Cinar 2,  Malliga R Iyer 1
Affiliations

Affiliations

  • 1 Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, Maryland 20852, United States.
  • 2 Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, Maryland 20852, United States.
  • 3 Laboratory of Biomolecular Structure and Pharmacology, Institute of Biochemistry, HUN-REN Biological Research Centre, Temesvari krt. 62, 6726 Szeged, Hungary.
  • 4 Université Bourgogne Europe, INSERM, Center for Translation and Molecular medicine (CTM), Team PAthophysiology of DYSlipidemia (PADYS), 21000 Dijon, France.
  • 5 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, United States.
  • 6 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 5625 Fishers Lane, Rockville, Maryland 20852, United States.
  • 7 Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
PMID: 41074851 DOI: 10.1021/acs.jmedchem.5c01158
Abstract

CB1 receptor antagonists that are peripherally acting hold promise for treating obesity, diabetes and fibrotic disorders highlighting their importance in treating metabolic syndrome disorders (MetS). We synthesized and evaluated compounds by integrating amidine fragments into 1,4,5,6-tetrahydropyridazine-based sulfonyl urea scaffolds for blocking CB1 receptors. Initial synthesis included compounds 10a-u, followed by expansion into distinct amidine groups (11a-18e) for detailed structure-activity relationships. The compounds displayed high CB1R binding affinity, potent CB1R antagonist activities and showed in vitro iNOS inhibition. Select compounds showed good oral exposure, with compound 11jE2 showing less than <13% brain penetrance, attesting to peripheral restriction. In vivo studies of four-arm antagonist 11jE2 revealed decreased food intake and body weight reduction in diet-induced obese (DIO) mice. Molecular docking and simulation analyses elucidated binding mechanisms, highlighting an unprecedented chair-boat conformation of the central core that may govern the actions in this series of compounds.

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