Design, Synthesis And Evaluation Of Periphery-selective CB1Receptor Antagonists

With the improvement of living standards, obesity has become aglobal epidemic. Obesity itself is not a disease, but diseases caused by obesityincluding type2diabetes, coronary heart disease, hypertension, cancer andpsychological problems caused by obesity body constitutes a great threat tohealth. A good diet and exercise may some extent participate to reduce obesity,but to develop anti-obesity drugs is in urgent priority. So far, anti-obesity drugssuch as Sibutramine and Rimonabant has been withdrawn from the marketbecause of severe side effects. Orlistat, the only drug exsists in clinical, hadlimited efficacy and the side effects on gastrointestinal tract. Thererfore, todevelop new anti-obesity drugs with high efficiency, low side-effects and goodclinical tolerance have great significances. Study have confirmed that cannabinoid (CB) type1receptorendogenous ligand plays a dual regulatory role in food intake and energyconsumption. The cannabinoid receptor which is a7-transmembraneG-protein-coupled receptor, has CB1and CB2two subtypes. The CB1receptorwhich was related to food intake and metabolism, is mainly expressed in thecentral nervous system. The CB1receptor is also found in peripheral tissuessuch as livers, lungs and kidneys, which was related to energy metabolism. TheCB2receptor which is primarily involved in immune regulation andneurodegenerations, is mainly located in the immune tissues and cells withlower expression in the central nervous system.The first cannabinoid CB1antagonist Rimonabant shows highselectivity for CB1receptor. Clinical studies have confirmed rimonabant cansuppress food intake and reduce body weight through acting upon the centraland peripheral CB1receptors respectively. However, due to its central nervoussystem (CNS) side-effects, such as depression and anxiety, it was withdrawnfrom the market. But there is no doubt that the CB1receptor acts as a efficientanti-obesity target. The key to design novel CB1antagonists is to develop aideal strategy to overcome the drawbacks of its central side effects. Thus,discovery of CB1receptor antagonists with peripheral selectivity and highefficiency is becoming a new tendency in recent anti-obesity research. TM38837,a new peripheral-acting CB1receptor antagonist，shows poor blood-brain barrier permeability. The preclinical research showed that TM38837100mg hadno impact on CNS effects, which means this dose does not penetrate the brain.This confirms the assumption that cannabinoid type1antagonists have thepotential of treating several (metabolic) disorders without the central side effects,and should be further developed.According to the established structure-activity relationship, we choserimonabant and TM38837as lead compounds. By analyzing the similarity ofTM38837and Rimonabant, we have designed two kinds of new CB1antagonists by modifying3-position of them with higher hydrophilicity groupswith the expectation of acquiring higher efficiency and peripheral selectivity.In this study, we have synthesized a total of25compounds, and theirstructures have been confirmed by1H-NMR and ESI-MS.All the compounds had been evaluated on EGFP-CB1_U2OS cellsmodel, and preliminary biological evaluation indicated that the compounds ofseries Ⅰ showed low inhibitory activity on the whole, while the series Ⅱperformed better, and among them, BSH-5-10, BSH-5-14, BSH-5-29showedgood activity comparable to Rimonabant. By analyzing the structures and the activity data of the targetmolecules, we discussed the structure-activity relationship of the CB1antagonistpreliminarily. The difference in potency between the two classes of targetcompounds indicted that the pyrazole-C5position plays a significant role inbioactivity. The introduction of substituents with high polarity in thepyrazole-C5position might help to afford high Peripheral selectivity, but alsoled to lower activity. The benzene substitutent with a alkyl linker at thepyrazole-C3position of the target compound can increase its inhabit activity ofCB1receptor. Furthmore, prolonging the length of the linker chain might affordhigher activity.