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BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-13 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00080 Lawrence R. Marcin 1 , Jayakumar Warrier 2 , Srinivasan Thangathirupathy 2 , Jianliang Shi 3 , George N. Karageorge 1 , Bradley C. Pearce 1 , Alicia Ng 1 , Hyunsoo Park 3 , James Kempson 3 , Jianqing Li 3 , Huiping Zhang 3 , Arvind Mathur 3 , Aliphedi B. Reddy 2 , G. Nagaraju 2 , Gopikishan Tonukunuru 2 , Grandhi V. R. K. M. Gupta 2 , Manjunatha Kamble 2 , Raju Mannoori 2 , Srinivas Cheruku 2 , Srinivas Jogi 2 , Jyoti Gulia 2 , Tanmaya Bastia 2 , Charulatha Sanmathi 2 , Jayant Aher 2 , Rajareddy Kallem 2 , Bettadapura N. Srikumar 2 , Kumar Kuchibhotla Vijaya 2 , Pattipati S. Naidu 2 , Mahesh Paschapur 2 , Narasimharaju Kalidindi 2 , Reeba Vikramadithyan 2 , Manjunath Ramarao 2 , Rex Denton 3 , Thaddeus Molski 1 , Eric Shields 1 , Murali Subramanian 2 , Xiaoliang Zhuo 1 , Michelle Nophsker 1 , Jean Simmermacher 1 , Michael Sinz 2 , Charlie Albright 1 , Linda J. Bristow 1 , Imadul Islam 2 , Joanne J. Bronson 1 , Richard E. Olson 1 , Dalton King 1 , Lorin A. Thompson 1 , John E. Macor 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-13 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00080 Lawrence R. Marcin 1 , Jayakumar Warrier 2 , Srinivasan Thangathirupathy 2 , Jianliang Shi 3 , George N. Karageorge 1 , Bradley C. Pearce 1 , Alicia Ng 1 , Hyunsoo Park 3 , James Kempson 3 , Jianqing Li 3 , Huiping Zhang 3 , Arvind Mathur 3 , Aliphedi B. Reddy 2 , G. Nagaraju 2 , Gopikishan Tonukunuru 2 , Grandhi V. R. K. M. Gupta 2 , Manjunatha Kamble 2 , Raju Mannoori 2 , Srinivas Cheruku 2 , Srinivas Jogi 2 , Jyoti Gulia 2 , Tanmaya Bastia 2 , Charulatha Sanmathi 2 , Jayant Aher 2 , Rajareddy Kallem 2 , Bettadapura N. Srikumar 2 , Kumar Kuchibhotla Vijaya 2 , Pattipati S. Naidu 2 , Mahesh Paschapur 2 , Narasimharaju Kalidindi 2 , Reeba Vikramadithyan 2 , Manjunath Ramarao 2 , Rex Denton 3 , Thaddeus Molski 1 , Eric Shields 1 , Murali Subramanian 2 , Xiaoliang Zhuo 1 , Michelle Nophsker 1 , Jean Simmermacher 1 , Michael Sinz 2 , Charlie Albright 1 , Linda J. Bristow 1 , Imadul Islam 2 , Joanne J. Bronson 1 , Richard E. Olson 1 , Dalton King 1 , Lorin A. Thompson 1 , John E. Macor 1
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There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.
中文翻译：
BMS-986163，GluN2B的负变构调节剂，在严重抑郁症中具有潜在用途
对于更有效和快速作用的抗抑郁药存在严重的未满足的医学需求。为此目的，所述的负变构调节剂Ñ甲基d天冬氨酸受体亚型GluN2B已经证明令人鼓舞的治疗潜力。我们在此报告了水溶性静脉前药BMS-986163（6）及其活性母体分子BMS-986169（5）的发现和临床前概况，证明其对GluN2B变构位点具有高结合亲和力（K i = 4.0 nM）和选择性抑制细胞中的GluN2B受体功能（IC 50 = 24 nM）。前药6向母体5的转化在临床前物种的体外和体内反应迅速。静脉内给药后，化合物5和6在啮齿动物中表现出稳定的离体GluN2B靶标结合水平，并在小鼠中表现出抗抑郁样活性。观察到无显著脱靶活性5，6，或主要代谢物的循环满足-1和满足-2 。前药BMS-986163（6）已显示出可接受的安全性和毒理学特征，并被选作临床前候选药物，用于进一步评估重度抑郁症。
更新日期：2018-04-13
中文翻译：
BMS-986163，GluN2B的负变构调节剂，在严重抑郁症中具有潜在用途
对于更有效和快速作用的抗抑郁药存在严重的未满足的医学需求。为此目的，所述的负变构调节剂Ñ甲基d天冬氨酸受体亚型GluN2B已经证明令人鼓舞的治疗潜力。我们在此报告了水溶性静脉前药BMS-986163（6）及其活性母体分子BMS-986169（5）的发现和临床前概况，证明其对GluN2B变构位点具有高结合亲和力（K i = 4.0 nM）和选择性抑制细胞中的GluN2B受体功能（IC 50 = 24 nM）。前药6向母体5的转化在临床前物种的体外和体内反应迅速。静脉内给药后，化合物5和6在啮齿动物中表现出稳定的离体GluN2B靶标结合水平，并在小鼠中表现出抗抑郁样活性。观察到无显著脱靶活性5，6，或主要代谢物的循环满足-1和满足-2 。前药BMS-986163（6）已显示出可接受的安全性和毒理学特征，并被选作临床前候选药物，用于进一步评估重度抑郁症。
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