title: Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jack D
authors.identifier: 0000-0002-7678-9699
authors.initials: JD
authors.lastname: Scott
authors.affiliation: Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Duane E
authors.initials: DE
authors.lastname: DeMong
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Greshock
authors.affiliation: Merck & Co., Inc. , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Kallol
authors.initials: K
authors.lastname: Basu
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Harris
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Li
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sue-Ing
authors.initials: SI
authors.lastname: Lin
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Macala
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Honglu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Merck & Co., Inc. , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Walsh
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Poirier
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhi-Cai
authors.initials: ZC
authors.lastname: Shi
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Gautam
authors.initials: G
authors.lastname: Agnihotri
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Marco A S
authors.initials: MA
authors.lastname: Baptista
authors.affiliation: Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: John
authors.initials: J
authors.lastname: Columbus
authors.affiliation: Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fell
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Mirescu
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Morrow
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhizhang
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Chang
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Embrey
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: John M
authors.identifier: 0000-0002-3788-4220
authors.initials: JM
authors.lastname: Sanders
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Tiscia
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drolet
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Kern
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Sur
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.affiliation: Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kennedy
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Miller
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2