Design and synthesis of peripherally selective dual CB1R antagonist/iNOS inhibitors for Metabolic disorders

Authors

• S Yaghoubi
• K Heselmeyer-Haddad
• I Archilla
• C Parra
• D Wangsa
• G Castellano
• S Lahoz
• V Pablo-Fontecha
• D Hirsch
• W Chen
• T Ried
• M Cuatrecasas
• PS Meltzer
• J Camps

Abstract

There is a pressing need for innovative therapeutic approaches to the growing global epidemic of obesity. As part of the endocannabinoid system, cannabinoid receptors are involved in a wide range of physiological and pathological processes in the human body. Through a lot of research and development on CB1 and CB2 ligands, different synthetic cannabinoid molecules with different affinities have been found. These molecules may be useful for treating a wide range of disorders. However, few of these ligands have found their way into clinical practice. CB1R inverse agonist Rimonabant became the first-in-class molecule approved in the EU as an anti-obesity drug. However, despite its pronounced therapeutic potential, it was withdrawn from the market in 2008 due to its adverse neuropsychiatric side effects. Literature precedent suggests that peripheral blockade of CB1 receptors retains many metabolic benefits without causing CNS side effects and achieves positive benefits like weight loss, less insulin resistance, and better control of glucose. Our main goal is to make CB1R inhibitors with peripheral restrictions. Radioligand binding and GTPγS functional assays were used to investigate a novel series of peripherally limited CB1R antagonists with a diaryl-pyridazine core and a sulfonamide moiety. Several synthesized analogues demonstrated strong CB1R binding affinities (Ki <10 nM, IC50 <15 nM), confirming in silico studies. Based on our preliminary in vitro and in vivo ADME data, we found many chiral antagonists with nanomolar affinity and selectivity for CB1R and functional antagonists at this receptor that may be able to cure fibrosis, diabetes, and obesity.

Scientific Focus Area: Molecular Pharmacology

This page was last updated on Monday, September 25, 2023