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

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.
Robert K Leśniak 1,  R Jeremy Nichols 2,  Marcus Schonemann 2,  Jing Zhao 2,  Chandresh R Gajera 2,  Grace Lam 3,  Khanh C Nguyen 3,  J William Langston 4,  Mark Smith 5,  Thomas J Montine 2
Affiliations

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: [email protected].
  • 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.

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