Design,Synthesis And SAR Evaluation Of Novel CB2Swlective Ligands

Currently, treatment effectiveness for neuropathic and immunological pain is limited. Antidepressants, anticonvulsants, and opioids remain first-line treatment. All of these drugs have significant CNS side effects. Consequently, there remains an unmet medical need for agents that have higher efficacy/responder rate and with reduced side-effects compared with currently used drugs. Recently, however, cannabinoid receptor2(CB2) ligands emerged as new agents for the treatment of this pain. Several promising candidates are under clinical trials. Therefore, it is significant to design CB2selective ligands for the treatment of neuropathic and immunological pain.A series of pyridazine derivatives were designed and synthesized in the first of this dissertation using2-[(2,4-dichloro-phenyl)-amino]-N-[(tetrahydro-2H-pyran-4-yl) methyl]-4-(trifluoromethyl)-5-pyrimidine-carbox-amide (GW842166X), is one of the CB2-selective agonists that have survived in the phase Ⅱ clinical trials for the treatment of pain without exhibiting cannabbis-like behavioral effects, as the lead compound. The design based on the direction of the computational results and the conception of bio-isosterism.32novel compounds were synthesized and structurally characterized by1H NMR and MS. All compounds were tested for their in vitro CB2selective agonistic activities. Among them, EC50value of the compound C1was11.3μM while the lead compound was7.78μM using the same tested method. So the compound C1can act as the lead compound to have a further structural transformation to get novel agonists with improved potency and selectivity.In the second part, we applied the method of privileged structure-oriented to design the piperazine derivatives with the piperazine ring replacing diazepane ring. The substituents on the piperazine ring were studied to investigate their impact on binding affinities with CB2.32novel compounds were synthesized and structurally characterized by1H NMR and MS. All compounds were tested for their in vitro CB2 selective agonistic activities. Among them, the compound F2was the CB2full agonist with the EC50value of0.87μM. Consequently, the SAR results obtained from our work can serve as a basis for the design of novel CB2agonists.In the third part, the benzimidazole derivatives were designed and synthesized on the basis of the lead compound of the pyrazol-imine derivatives. The synthesized compounds were tested for their in vitro CB2selective antagonistic activities. Among them, the compounds G2and G3showed good CB2antagonistic activity. Consequently, the findings in the present work can serve as a guideline for the rational design of novel antagonists with improved potency and selectivity.