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

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

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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