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Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c01627 Kaitlyn M Logan 1 , Will Kaplan 1 , Vladimir Simov 1 , Hua Zhou 1 , Derun Li 1 , Luis Torres 1 , Gregori J Morriello 2 , John J Acton 2 , Barbara Pio 2 , Yi-Heng Chen 2 , Mitchell H Keylor 1 , Rebecca Johnson 1 , Solomon D Kattar 1 , Ryan Chau 1 , Xin Yan 1 , Michael Ardolino 1 , Cayetana Zarate 1 , Karin M Otte 1 , Rachel L Palte 1 , Tina Xiong 1 , Spencer E McMinn 1 , Shishi Lin 2 , Santhosh F Neelamkavil 2 , Ping Liu 1 , Jing Su 2 , Laxminarayan G Hegde 1 , Janice D Woodhouse 1 , Lily Y Moy 1 , Paul J Ciaccio 1 , Jennifer Piesvaux 1 , Matthias Zebisch 3 , Clare Henry 3 , John Barker 3 , Harold B Wood 2 , Matthew E Kennedy 1 , Erin F DiMauro 1 , Matthew J Fell 1 , Peter H Fuller 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c01627 Kaitlyn M Logan 1 , Will Kaplan 1 , Vladimir Simov 1 , Hua Zhou 1 , Derun Li 1 , Luis Torres 1 , Gregori J Morriello 2 , John J Acton 2 , Barbara Pio 2 , Yi-Heng Chen 2 , Mitchell H Keylor 1 , Rebecca Johnson 1 , Solomon D Kattar 1 , Ryan Chau 1 , Xin Yan 1 , Michael Ardolino 1 , Cayetana Zarate 1 , Karin M Otte 1 , Rachel L Palte 1 , Tina Xiong 1 , Spencer E McMinn 1 , Shishi Lin 2 , Santhosh F Neelamkavil 2 , Ping Liu 1 , Jing Su 2 , Laxminarayan G Hegde 1 , Janice D Woodhouse 1 , Lily Y Moy 1 , Paul J Ciaccio 1 , Jennifer Piesvaux 1 , Matthias Zebisch 3 , Clare Henry 3 , John Barker 3 , Harold B Wood 2 , Matthew E Kennedy 1 , Erin F DiMauro 1 , Matthew J Fell 1 , Peter H Fuller 1
Affiliation
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Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment of Parkinson’s disease. We previously disclosed the discovery of an indazole series lead that demonstrated both safety and translational risks. The safety risks were hypothesized to be of unknown origin, so structural diversity in subsequent chemical matter was prioritized. The translational risks were identified due to a low brain Kpu,u in nonhuman primate studies, which raised concern over the use of an established peripheral biomarker as a surrogate for central target engagement. Given these challenges, the team sought to leverage structure- and property-based drug design and expanded efflux transporter profiling to identify structurally distinct leads with enhanced CNS drug-likeness. Herein, we describe the discovery of a “reinvented” indazole series with improved physicochemical properties and efflux transporter profiles while maintaining excellent potency and off-target kinase selectivity, which resulted in advanced lead, compound 23.
中文翻译：
N-杂芳基茚达唑 LRRK2 抑制剂的发现和优化
抑制富含亮氨酸的重复激酶 2 是治疗帕金森病的一种遗传支持机制。我们之前披露了一种吲咪唑系列先导化合物的发现，该先导化合物证明了安全性和转化风险。假设安全风险来源不明，因此优先考虑后续化学物质的结构多样性。由于非人灵长类动物研究中大脑 Kpu，u 低，因此确定了翻译风险，这引起了人们对使用已建立的外周生物标志物作为中心靶点参与的替代物的担忧。鉴于这些挑战，该团队试图利用基于结构和特性的药物设计以及扩展的外排转运蛋白分析来识别结构不同的线索，并增强 CNS 药物相似性。在本文中，我们描述了一种“重新发明”的吲咪唑系列的发现，该系列具有改进的理化性质和外排转运蛋白谱，同时保持出色的效力和脱靶激酶选择性，从而产生了高级铅化合物 23。
更新日期：2024-09-04
中文翻译：
N-杂芳基茚达唑 LRRK2 抑制剂的发现和优化
抑制富含亮氨酸的重复激酶 2 是治疗帕金森病的一种遗传支持机制。我们之前披露了一种吲咪唑系列先导化合物的发现，该先导化合物证明了安全性和转化风险。假设安全风险来源不明，因此优先考虑后续化学物质的结构多样性。由于非人灵长类动物研究中大脑 Kpu，u 低，因此确定了翻译风险，这引起了人们对使用已建立的外周生物标志物作为中心靶点参与的替代物的担忧。鉴于这些挑战，该团队试图利用基于结构和特性的药物设计以及扩展的外排转运蛋白分析来识别结构不同的线索，并增强 CNS 药物相似性。在本文中，我们描述了一种“重新发明”的吲咪唑系列的发现，该系列具有改进的理化性质和外排转运蛋白谱，同时保持出色的效力和脱靶激酶选择性，从而产生了高级铅化合物 23。
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