1. Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors.
- Author
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Ding X, Stasi LP, Ho MH, Zhao B, Wang H, Long K, Xu Q, Sang Y, Sun C, Hu H, Yu H, Wan Z, Wang L, Edge C, Liu Q, Li Y, Dong K, Guan X, Tattersall FD, Reith AD, and Ren F
- Subjects
- Administration, Oral, Animals, Biological Availability, Brain drug effects, Brain metabolism, Dose-Response Relationship, Drug, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism, Mice, Molecular Structure, Phosphorylation drug effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Rats, Serine antagonists & inhibitors, Serine metabolism, Structure-Activity Relationship, Drug Discovery, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration., (Copyright © 2018. Published by Elsevier Ltd.)
- Published
- 2018
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