JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 19; pp. 6173 - 6180
• Main Authors: Chorvat, Robert J., Berbaum, Jennifer, Seriacki, Kristine, McElroy, John F.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2012; Elsevier
• Subjects: agonists; Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Biological and medical sciences; brain; Brain Diseases, Metabolic - drug therapy; CB1 antagonist; CB1 receptor inverse agonist; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Diabetes; Dose-Response Relationship, Drug; Dyslipidemias; enzymes; glucose tolerance; Humans; insulin resistance; JD-5006; JD-5037; Life Sciences & Biomedicine; liver; Liver diseases; Medical sciences; Metabolic disorders; Molecular Structure; Obesity; Peripherally restricted cannabinoid-1 receptor blockers; pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; receptors; Recombinant Proteins - agonists; Recombinant Proteins - antagonists & inhibitors; Rimonabant; Science & Technology; SLV-319; Structure-Activity Relationship; structure-activity relationships; Sulfonamides; therapeutics; tissue distribution; triacylglycerols; Obesity; CB1 antagonist; Liver diseases; Dyslipidemias; Rimonabant; CB1 receptor inverse agonist; Diabetes; JD-5037; JD-5006; SLV-319; Metabolic disorders; Peripherally restricted cannabinoid-1 receptor blockers; CARDIOMETABOLIC RISK; AGONISTS; DISCOVERY; CB2 RECEPTORS; 1 ANTAGONISTS; DRUGS; BRAIN PENETRATION; GLYCOPROTEIN; WEIGHT; Endocrinopathy; CB1 cannabinoid receptor; Lipids; Hepatic disease; Prokinetic agent; Ibipinabant; Cannabinoid receptor; Antagonist; Dyslipemia; Nutritional status; Diabetes mellitus; Nutrition disorder; Metabolic diseases; Digestive transit; Metabolic disorder; Treatment; Inverse agonist; Digestive diseases; Anorectic
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.08.004

Analogs of SLV-319 (Ibipinibant), a CB1 receptor inverse agonist, were synthesized with functionality intended to limit brain exposure while maintaining the receptor affinity and selectivity of the parent compound. Structure–activity relationships of this series, and pharmacology of two lead compounds, 16 (JD-5006) and 23 (JD-5037) showing little brain presence as indicated by tissue distribution and receptor occupancy studies, are described. Effects with one of these compounds on plasma triglyceride levels, liver weight and enzymes, glucose tolerance and insulin sensitivity support the approach that blockade of peripheral CB1 receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB1 blockers. Thus, PR CB1 inverse agonists may indeed represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity. Analogs of SLV-319 (Ibipinibant), a CB1 receptor inverse agonist, were synthesized with functionality intended to limit brain exposure while maintaining the receptor affinity and selectivity of the parent compound. Structure activity relationships of this series, and pharmacology of two lead compounds, 16 (JD-5006) and 23 (JD-5037) showing little brain presence as indicated by tissue distribution and receptor occupancy studies, are described. Effects with one of these compounds on plasma triglyceride levels, liver weight and enzymes, glucose tolerance and insulin sensitivity support the approach that blockade of peripheral CB1 receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB1 blockers. Thus, PR CB1 inverse agonists may indeed represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity.