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.

Autor:	Scott JD; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., DeMong DE; Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Greshock TJ; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Basu K; Merck & Co., Inc. , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Dai X; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Harris J; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Hruza A; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Li SW; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Lin SI; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Liu H; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Macala MK; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Hu Z; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Mei H; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Zhang H; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Walsh P; Merck & Co., Inc. , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Poirier M; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Shi ZC; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Xiao L; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Agnihotri G; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Baptista MA; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Columbus J; Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Fell MJ; Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Hyde LA; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Kuvelkar R; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Lin Y; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Mirescu C; Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Morrow JA; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Yin Z; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Zhang X; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Zhou X; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Chang RK; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Embrey MW; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Sanders JM; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Tiscia HE; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Drolet RE; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Kern JT; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Sur SM; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Renger JJ; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Bilodeau MT; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Kennedy ME; Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Parker EM; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Stamford AW; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Nargund R; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., McCauley JA; Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Miller MW; Merck & Co., Inc. , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Apr 13; Vol. 60 (7), pp. 2983-2992. Date of Electronic Publication: 2017 Mar 16.
DOI:	10.1021/acs.jmedchem.7b00045
Abstrakt:	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.
Databáze:	MEDLINE
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