新型静脉注射用谷氨酸-N-甲基-D-天冬氨酸2B受体负变构调节剂()-3-((3,4)-3-氟-4-(4-羟基苯基)哌啶-1-基)-1-(4-甲基苄基)吡咯烷-2-酮（BMS-986169）在重度抑郁症中的临床前特性研究
Preclinical Characterization of ()-3-((3,4)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate -Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.
作者信息
Bristow Linda J, Gulia Jyoti, Weed Michael R, Srikumar Bettadapura N, Li Yu-Wen, Graef John D, Naidu Pattipati S, Sanmathi Charulatha, Aher Jayant, Bastia Tanmaya, Paschapur Mahesh, Kalidindi Narasimharaju, Kumar Kuchibhotla Vijaya, Molski Thaddeus, Pieschl Rick, Fernandes Alda, Brown Jeffrey M, Sivarao Digavalli V, Newberry Kimberly, Bookbinder Mark, Polino Joseph, Keavy Deborah, Newton Amy, Shields Eric, Simmermacher Jean, Kempson James, Li Jianqing, Zhang Huiping, Mathur Arvind, Kallem Raja Reddy, Sinha Meenakshee, Ramarao Manjunath, Vikramadithyan Reeba K, Thangathirupathy Srinivasan, Warrier Jayakumar, Islam Imadul, Bronson Joanne J, Olson Richard E, Macor John E, Albright Charlie F, King Dalton, Thompson Lorin A, Marcin Lawrence R, Sinz Michael
机构信息
Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.)
Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.).
出版信息
J Pharmacol Exp Ther. 2017 Dec;363(3):377-393. doi: 10.1124/jpet.117.242784. Epub 2017 Sep 27.
()-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3,4)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (K = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human -methyl-d-aspartate receptor subtypes (IC = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC = 28.4 M) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo 3H-5-methyl-10,11-dihydro-5H-dibenzo[]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
()-3-((3S,4S)-3-氟-4-(4-羟基苯基)哌啶-1-基)-1-(4-甲基苄基)吡咯烷-2-酮(BMS-986169)和磷酸前药4-((3,4)-3-氟-1-((R)-1-(4-甲基苄基)-2-氧代吡咯烷-3-基)哌啶-4-基)苯基磷酸二氢盐(BMS-986163)是在一项药物研发工作中鉴定出来的，该工作专注于开发新型静脉注射型谷氨酸-N-甲基-D-天冬氨酸2B受体(GluN2B)负变构调节剂(NAMs)用于治疗抵抗性抑郁症(TRD)。BMS-986169对GluN2B亚基变构调节位点表现出高结合亲和力(K = 4.03 - 6.3 nM)，并在表达人N-甲基-D-天冬氨酸受体亚型的非洲爪蟾卵母细胞中选择性抑制GluN2B受体功能(IC = 24.1 nM)。BMS-986169对人醚-去极化相关基因通道活性的抑制作用较弱(IC = 28.4 μM)，并且在包含40个其他药理学靶点的检测组中活性可忽略不计。静脉注射BMS-986169或BMS-986163剂量依赖性地增加GluN2B受体占有率，并抑制体内3H-5-甲基-10,11-二氢-5H-二苯并[]环庚烯-5,10-亚胺([3H]MK-801)结合，证实了靶点结合和前药的有效裂解。BMS-986169在小鼠强迫游泳试验中减少了不动时间，这一效应与静脉注射氯胺酮治疗相似。新奇抑制进食潜伏期缩短，并且在急性给予BMS-986163或BMS-986169 24小时后还观察到离体海马长时程增强增加。BMS-986169在小鼠或食蟹猴中未产生氯胺酮样的运动亢进或异常行为，但在猴中确实产生了与血浆暴露密切相关的短暂工作记忆损害。最后，BMS-986163在定量脑电图功率谱分布上产生了显著变化，这是一种可用于评估健康人体内药效学活性的转化指标。由于BMS-986169的水溶性较差，BMS-986163被选为主要的GluN2B NAM候选药物，作为一种用于TRD的新型静脉注射剂进行进一步评估。
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