Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2) inhibitors possessing a key intramolecular hydrogen bond - Part 2

Daniel G M Shore; Zachary K Sweeney; Alan Beresford; Bryan K Chan; Huifen Chen; Jason Drummond; Andrew Gill; Tracy Kleinheinz; Xingrong Liu; Andrew D Medhurst; Edward G McIver; John G Moffat; Haitao Zhu; Anthony A Estrada

doi:10.1016/j.bmcl.2018.10.017

Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2) inhibitors possessing a key intramolecular hydrogen bond - Part 2

Bioorg Med Chem Lett. 2019 Feb 15;29(4):674-680. doi: 10.1016/j.bmcl.2018.10.017. Epub 2018 Oct 12.

Authors

Affiliations

¹ Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: shore.daniel@gene.com.
² Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
³ Department of Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK.
⁴ Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
⁵ Department of Biochemical and Cellular Pharmacology, BioFocus, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK.
⁶ Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
⁷ LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK.
⁸ Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

PMID: 30522953
DOI: 10.1016/j.bmcl.2018.10.017

Abstract

The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.

Keywords: Azaindazole; Brain penetration; Kinase inhibitor; LRRK2; Parkinson’s disease.

MeSH terms

Drug Discovery
Hydrogen Bonding
Indazoles / chemistry*
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*

Substances

Indazoles
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2