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.
- 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.
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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Cat. No.Product NameDescriptionTargetResearch Area
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target: LRRK2Research Areas: Neurological Disease
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target: LRRK2Research Areas: Neurological Disease