Doornbos Maarten L J, Cid José María, Haubrich Jordi, Nunes Alexandro, van de Sande Jasper W, Vermond Sophie C, Mulder-Krieger Thea, Trabanco Andrés A, Ahnaou Abdellah, Drinkenburg Wilhelmus H, Lavreysen Hilde, Heitman Laura H, IJzerman Adriaan P, Tresadern Gary
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University , P.O. Box 9502, 2300RA Leiden, The Netherlands.
Janssen Research and Development , Calle Jarama 75A, 45007, Toledo, Spain.
J Med Chem. 2017 Aug 10;60(15):6704-6720. doi: 10.1021/acs.jmedchem.7b00669. Epub 2017 Aug 1.
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k, k and residence time (RT) were determined. The PAMs showed various kinetic profiles; k values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu PAMs with high values for k but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.
我们报告了一系列具有亲代谢型谷氨酸受体（mGlu）正变构调节剂（PAM）活性和亲和力的7-芳基-1,2,4-三唑并[4,3-a]吡啶的合成及生物学评价。除了传统的体外效价和亲和力参数外，还测定了动力学参数k、k和驻留时间（RT）。这些PAM表现出各种动力学特征；k值范围超过2个数量级，而RT值在10倍范围内。结合速率常数k与亲和力呈线性相关。在无标记分析中对短、中、长RT化合物的评估表明RT与功能效应之间存在相关性。长RT化合物9对睡眠-觉醒状态的影响表明，长RT在体内转化为对快速眼动（REM）的持续抑制。这些结果表明，仅由亲和力驱动的选择可能会产生具有高k值但不一定具有优化RT的mGlu PAM，而RT是预测体内最佳疗效的关键。
