Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease, and diabetes. Recently, development of several CB1 antagonists was halted because of adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than that for rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization
