1. Academic Validation
  2. Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors

Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors

  • J Med Chem. 2024 Sep 26;67(18):16807-16819. 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
Affiliations

Affiliations

  • 1 Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2 Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey 07065, United States.
  • 3 Evotec (U.K.) Ltd., 90 Park Drive, Milton Park, Abingdon OX14 4RZ, Oxfordshire, U.K.
Abstract

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.

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