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
  • 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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