Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1 H-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease

  • J Med Chem. 2022 Dec 22;65(24):16801-16817. doi: 10.1021/acs.jmedchem.2c01605.
David A Candito  1 Vladimir Simov  1 Anmol Gulati  1 Solomon Kattar  1 Ryan W Chau  1 Blair T Lapointe  1 Joey L Methot  1 Duane E DeMong  1 Thomas H Graham  1 Ravi Kurukulasuriya  1 Mitchell H Keylor  1 Ling Tong  2 Gregori J Morriello  2 John J Acton  2 Barbara Pio  2 Weiguo Liu  2 Jack D Scott  2 Michael J Ardolino  1 Theodore A Martinot  1 Matthew L Maddess  1 Xin Yan  1 Hakan Gunaydin  1 Rachel L Palte  1 Spencer E McMinn  1 Lisa Nogle  1 Hongshi Yu  1 Ellen C Minnihan  1 Charles A Lesburg  1 Ping Liu  1 Jing Su  2 Laxminarayan G Hegde  1 Lily Y Moy  1 Janice D Woodhouse  1 Robert Faltus  1 Tina Xiong  1 Paul Ciaccio  1 Jennifer A Piesvaux  1 Karin M Otte  1 Matthew E Kennedy  1 David Jonathan Bennett  1 Erin F DiMauro  1 Matthew J Fell  1 Santhosh Neelamkavil  2 Harold B Wood  2 Peter H Fuller  1 J Michael Ellis  1
Affiliations
  • 1. Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts02115, United States.
  • 2. Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey07033, United States.
Abstract

Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.

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