Discovery and characterization of N-(1,3-dialkyl-1 H-indazol-6-y1)-1H-pyrazolo [4,3-b] pyridin-3-amine scaffold as mGlu(4) positive allosteric modulators that mitigate CYP1A2 induction liability

作者：Engers Darren W; Bollinger Sean R; Engers Julie L; Panaresea 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^*

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(15): 2641-2646.

DOI：10.1016/j.bmcl.2018.06.034

• mGlu4 PAM
• Positive allosteric modulator
• CYP induction
• Parkinson's disease
• Structure-activity relationship

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(4) PAMs, leading to 9i (hmGlu(4) EC50 = 43 nM; AhR activation = 2.3-fold).

• 出版日期2018-8-15