CRB-913

CRB-913 is a second-generation, highly peripherally restricted small molecule inverse agonist of the cannabinoid type 1 receptor (CB1). It is being developed as an oral therapy for obesity and related metabolic conditions. Unlike first-generation CB1 inverse agonists such as rimonabant, which were discontinued due to neuropsychiatric side effects from central nervous system penetration, CRB-913 has been engineered to minimize brain exposure—demonstrating a brain-to-plasma ratio up to 50 times lower than rimonabant and 15 times lower than monlunabant. Preclinical studies show that CRB-913 reduces body weight in diet-induced obese mice both as monotherapy and in combination with incretin analogs (tirzepatide, semaglutide, liraglutide), with improvements in body fat content, insulin resistance, liver triglycerides, and liver histology. The drug acts by selectively binding CB1 receptors (IC50 = 1.2 nM for CB1 vs >1000 nM for CB2) and exhibits high potency in cAMP inverse agonist and β-arrestin antagonist assays[1][2][3][4][5][6].