Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor.

Autor: Chan BK; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Estrada AA; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Chen H; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Atherall J; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Baker-Glenn C; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Beresford A; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Burdick DJ; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Chambers M; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Dominguez SL; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Drummond J; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Gill A; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Kleinheinz T; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Le Pichon CE; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Medhurst AD; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Liu X; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Moffat JG; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Nash K; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Scearce-Levie K; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Sheng Z; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Shore DG; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Van de Poël H; Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom., Zhang S; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Zhu H; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States., Sweeney ZK; Departments of Discovery Chemistry, Biochemical and Cellular Pharmacology, Drug Metabolism and Pharmacokinetics, and Neuroscience, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2012 Nov 23; Vol. 4 (1), pp. 85-90. Date of Electronic Publication: 2012 Nov 23 (Print Publication: 2013).
DOI: 10.1021/ml3003007
Abstrakt: The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs.
Databáze: MEDLINE
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