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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