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Triazolopyridazine LRRK2 kinase inhibitors |
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| Authors: | Maurizio Franzini Xiaocong M Ye Marc Adler Danielle L Aubele Albert W Garofalo Shawn Gauby Erich Goldbach Gary D Probst Kevin P Quinn Pam Santiago Hing L Sham Danny Tam Anh Truong Zhao Ren |
| Institution: | 1. Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States;2. Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States;3. Department of Drug Metabolism and Pharmacokinetics, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States;4. Department of Assay Development, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States |
| Abstract: | Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson’s disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of 1,2,4]triazolo4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed. |
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