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. 2023 Oct 15:95:129487.
doi: 10.1016/j.bmcl.2023.129487. Epub 2023 Sep 19.

Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity

Albert W Garofalo  1 , Jacob Schwarz  2 , Kerry Zobel  2 , Claudia Beato  3 , Silvia Bernardi  3 , Federica Budassi  3 , Laura Caberlotto  3 , Peng Gao  4 , Cristiana Griffante  3 , Xinying Liu  4 , Marco Migliore  3 , Feifei Qiao  4 , Fabio Maria Sabbatini  3 , Anna Sava  3 , Mingliang Zhang  4 , Holly J Carlisle  2
Affiliations

Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity

Albert W Garofalo et al. Bioorg Med Chem Lett. .

Abstract

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

Keywords: G2019S; Kinase inhibitor; LRRK2; Parkinson’s disease.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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