Bhattacharjee, Pinaki and Dvorácskó, Szabolcs and Volesky, Paul and Pointeau, Oceane and Rutland, Nicholas and Maccioni, Luca and Godlewski, Grzegorz and Jourdan, Tony and Hassan, Sergio A. and Cinar, Resat and Iyer, Malliga R. (2025) Leveraging Peripheral CB1 Antagonism in 1,4,5,6-Tetrahydropyridazine-Based Amidine Substituted Sulfonyl Analogs for Treating Metabolic Disorders. JOURNAL OF MEDICINAL CHEMISTRY, 68 (20). pp. 21224-21248. ISSN 0022-2623
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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.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: U.S. Department of Health and Human Services; Intramural Research Program of the National Institutes of Health (NIH) [ZIA AA000360, Z1A AA000355]; National Institute on Alcohol Abuse and Alcoholism (NIAAA); Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences [PD 139012]; National Research, Development and Innovation Office Funding text: This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. Intramural funds from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to M.R.I (ZIA AA000360) and R.C (Z1A AA000355) are acknowledged. S. D. is currently supported by the Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences and by the National Research, Development and Innovation Office (PD 139012). For help with HRMS data and NMR experiments, we thank John Lloyd and Dr. Walter Teague respectively. We thank Judy Harvey-White for technical assistance with mass spectrometry experiments. This study utilized the high-performance computational capabilities of the Biowulf HPC cluster (https://hpc.nih.gov). |
| Uncontrolled Keywords: | Brain; DISEASE; SYSTEM; NITRIC-OXIDE SYNTHASE; RECEPTOR; SURFACE; Fibrosis; rimonabant; INOS; |
| Subjects: | Q Science / természettudomány > QD Chemistry / kémia R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 24 Sep 2026 09:42 |
| Last Modified: | 24 Sep 2026 09:42 |
| URI: | https://real.mtak.hu/id/eprint/247467 |
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