Triazolopyridazine LRRK2 kinase inhibitors

被引：25

作者：

Franzini, Maurizio ^{[1
]}

Ye, Xiaocong M. ^{[1
]}

Adler, Marc ^{[2
]}

Aubele, Danielle L. ^{[1
]}

Garofalo, Albert W. ^{[1
]}

Gauby, Shawn ^{[3
]}

Goldbach, Erich ^{[3
]}

Probst, Gary D. ^{[1
]}

Quinn, Kevin P. ^{[3
]}

Santiago, Pam ^{[3
]}

Sham, Hing L. ^{[1
]}

Tam, Danny ^{[4
]}

Anh Truong ^{[1
]}

Ren, Zhao ^{[4
]}

机构：

[1] Elan Pharmaceut, Dept Med Chem, San Francisco, CA 94080 USA

[2] Elan Pharmaceut, Dept Mol Design, San Francisco, CA 94080 USA

[3] Elan Pharmaceut, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[4] Elan Pharmaceut, Dept Assay Dev, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 07期

关键词：

LRRK2; Parkinson's; Inhibition; Kinase; Treatment; Discovery; Wild-type; G2019S mutant; Phosphorylation; SAR; Activity; Selectivity; Bioisostere; Hinge; HTS; Oxidative metabolism; Binding mode; Synthesis; CENTER-DOT-LICL; PARKINSONS-DISEASE; HETEROAROMATICS; AROMATICS; ZINCATION; TARGETS; BINDING;

D O I：

10.1016/j.bmcl.2013.02.043

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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]triazolo[4,3-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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1967 / 1973

页数：7

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