Discovery of azaspirocyclic 1H-3,4,5-Trisubstitued pyrazoles as novel G2019S-LRRK2 selective kinase inhibitors

Robert K Leśniak; R Jeremy Nichols; Marcus Schonemann; Jing Zhao; Chandresh R Gajera; Grace Lam; Khanh C Nguyen; J William Langston; Mark Smith; Thomas J Montine

doi:10.1016/j.ejmech.2022.114693

Discovery of azaspirocyclic 1H-3,4,5-Trisubstitued pyrazoles as novel G2019S-LRRK2 selective kinase inhibitors

Eur J Med Chem. 2022 Nov 15:242:114693. doi: 10.1016/j.ejmech.2022.114693. Epub 2022 Aug 24.

Authors

Affiliations

¹ Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, CA, 94305, USA; Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA. Electronic address: r.k.lesniak@stanford.edu.
² Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
³ Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁴ Department of Pathology, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA; Department of Neurology and Neuroscience, 300 Pasteur Drive, Stanford University, Stanford, CA, 94304, USA.
⁵ Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, Stanford, CA, 94305, USA.

PMID: 36049274
DOI: 10.1016/j.ejmech.2022.114693

Abstract

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.

Keywords: Bioisosteres; Kinase inhibitors; LRRK2; Peptides and proteins; Selectivity.

MeSH terms

Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
Mutation
Parkinson Disease* / drug therapy
Protein Kinase Inhibitors / metabolism
Pyrazoles / pharmacology
Pyrazoles / therapeutic use
Sulfonamides / pharmacology
Sulfonamides / therapeutic use

Substances

Protein Kinase Inhibitors
Pyrazoles
Sulfonamides
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2