Engers Darren W, Bollinger Sean R, Engers Julie L, Panarese Joseph D, Breiner Megan M, Gregro Alison, Blobaum Anna L, Bronson Joanne J, Wu Yong-Jin, Macor John E, Rodriguez Alice L, Zamorano Rocio, Conn P Jeffrey, Lindsley Craig W, Niswender Colleen M, Hopkins Corey R
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2018 Aug 15;28(15):2641-2646. doi: 10.1016/j.bmcl.2018.06.034. Epub 2018 Jun 19.
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu PAMs, leading to 9i (hmGlu EC = 43 nM; AhR activation = 2.3-fold).
我们实验室之前的报告揭示了一种新型1H-吡唑并[4,3-b]吡啶-3-胺支架（VU8506）的结构和活性，该支架在帕金森病临床前啮齿动物模型中显示出优异的效力、选择性和体内疗效。不幸的是，通过上游芳烃受体（AhR）激活测定，该化合物具有显著的CYP1A2诱导作用（125倍），因此在慢性研究中被排除进一步研发。在此，我们报告一种最近开发的新支架，为减轻早期支架中存在的CYP1A2缺陷而对其进行了系统研究。我们已经鉴定出一种新型结构，该结构保持了其他代谢型谷氨酸受体（mGlu）正性变构调节剂（PAMs）的效力和选择性，从而得到化合物9i（hmGlu EC = 43 nM；AhR激活 = 2.3倍）。
