King Dalton, Iwuagwu Christiana, Cook Jim, McDonald Ivar M, Mate Robert, Zusi F Christopher, Hill Matthew D, Fang Haiquan, Zhao Rulin, Wang Bei, Easton Amy E, Miller Regina, Post-Munson Debra, Knox Ronald J, Gallagher Lizbeth, Westphal Ryan, Molski Thaddeus, Fan Jingsong, Clarke Wendy, Benitex Yulia, Lentz Kimberley A, Denton Rex, Morgan Daniel, Zaczek Robert, Lodge Nicholas J, Bristow Linda J, Macor John E, Olson Richard E
Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
ACS Med Chem Lett. 2017 Feb 8;8(3):366-371. doi: 10.1021/acsmedchemlett.7b00032. eCollection 2017 Mar 9.
The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT receptor (>300-fold). activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.
精神分裂症相关阴性症状和认知功能障碍的治疗是一项重大未满足医疗需求。临床前文献表明，α7神经元烟碱型乙酰胆碱（nACh）受体激动剂可能为治疗精神分裂症认知功能障碍提供有效方法。我们在此报告（BMS-933043）的发现与评估，它是一种新型强效α7 nACh受体部分激动剂，对其他烟碱型乙酰胆碱受体亚型（>100倍）和5-羟色胺受体（>300倍）具有高选择性。在认知障碍的临床前模型小鼠新物体识别实验中证明了其活性。BMS-933043已完成I期临床试验。
