2. Academic Validation
  3. 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.
PMID: 36475697 DOI: 10.1021/acs.jmedchem.2c01605
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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