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Bioorg Med Chem Lett. 2016 Jun 1;26(11):2631-5. doi: 10.1016/j.bmcl.2016.04.021. Epub 2016 Apr 9.

Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors.

Author information

1
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States. Electronic address: thomas_greshock@merck.com.
2
Department of Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States. Electronic address: john_sanders@merck.com.
3
Department of Neuroscience Research, Merck Research Laboratories, West Point, PA 19486, United States.
4
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
5
Department of Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
6
Department of In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
7
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.

Abstract

Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.

KEYWORDS:

CNS; Kinase; LRRK2; Leucine rich repeat kinase; Parkinson’s disease

PMID:
27106707
DOI:
10.1016/j.bmcl.2016.04.021
[Indexed for MEDLINE]

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