Yan Lin, Pan Miaobo, Fu Mian, Wang Jingjie, Huang Wenlong, Qian Hai
Institute of Chemistry & Biology, Henan University, Kaifeng 475004, China.
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Bioorg Med Chem. 2016 Feb 15;24(4):849-57. doi: 10.1016/j.bmc.2016.01.009. Epub 2016 Jan 6.
Multitarget-directed ligands might offer certain advantages over traditional single-target drugs and/or drug combinations. In the present study, a series of novel analgesic agents targeting both cyclooxygenase and TRPV1 were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazine, ethanediamine cores. These compounds were evaluated for antagonism of hTRPV1 activation by capsaicin and the ability to inhibit Ovine COX-1 and human recombinant COX-2 in vitro. The favorable potentials of these test compounds were further characterized in preliminary analgesic and side-effects tests in vivo. On the basis of comprehensive evaluations, compound 8d which showed strong TRPV1 antagonistic activity, middle COX-2 inhibition, weak ulcerogenic action and had no hyperthermia side-effect was considered as a safe candidate for the further development of analgesic drugs.
多靶点导向配体可能比传统的单靶点药物和/或药物组合具有某些优势。在本研究中，制备并评估了一系列同时靶向环氧化酶和瞬时受体电位香草酸亚型1（TRPV1）的新型镇痛药，以优化先前描述的以哌嗪、乙二胺为核心的先导化合物的性质。评估了这些化合物对辣椒素激活人TRPV1的拮抗作用以及在体外抑制绵羊COX-1和人重组COX-2的能力。在初步的体内镇痛和副作用试验中进一步表征了这些受试化合物的良好潜力。基于综合评估，化合物8d表现出较强的TRPV1拮抗活性、中等的COX-2抑制作用、较弱的致溃疡作用且无发热副作用，被认为是镇痛药进一步开发的安全候选物。
