title: Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor.
abstract: 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.
authors.affiliation: 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.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.affiliation: 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.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Atherall
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Baker-Glenn
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Beresford
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Chambers
authors.affiliation: 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.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Dominguez
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gill
authors.affiliation: 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.
authors.forename: Tracy
authors.initials: T
authors.lastname: Kleinheinz
authors.affiliation: 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.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Le Pichon
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.affiliation: 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.
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Nash
authors.affiliation: 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.affiliation: 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.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Shore
authors.affiliation: Departments of Chemistry, Biochemical and Cellular Pharmacology, and Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park , Saffron Walden, Essex CB10 1XL, United Kingdom.
authors.forename: Hervé
authors.initials: H
authors.lastname: Van de Poël
authors.affiliation: 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.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
keywords: CYP1A2 inhibition; LRRK2; Parkinson’s disease; kinase inhibitor