Structure-activity relationship (SAR) studies on substituted N-(pyridin-3-yl)-2-amino-isonicotinamides as highly potent and selective glycogen synthase kinase-3 (GSK-3) inhibitors

被引：9

作者：

Luo, Guanglin ^{[1
,2
]}

Chen, Ling ^{[1
,2
]}

Jacutin-Porte, Swanee ^{[1
,3
]}

Han, Ying ^{[1
]}

Burton, Catherine R. ^{[1
]}

Xiao, Hong ^{[1
]}

Krause, Carol M. ^{[1
,2
]}

Cao, Yang ^{[1
]}

Liu, Nengyin ^{[1
]}

Kish, Kevin ^{[2
]}

Lewis, Hal A. ^{[2
]}

Macor, John E. ^{[1
]}

Dubowchik, Gene M. ^{[1
]}

机构：

[1] Bristol Myers Squibb, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb, Lawrenceville, NJ 08543 USA

[3] Bristol Myers Squibb, Cambridge, MA 02142 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2023年 / 81卷

关键词：

GSK-3; inhibitor; Isonicotinamide; SAR studies; Alzheimer?s disease; DISCOVERY; 3-BETA; TARGET; TAU;

D O I：

10.1016/j.bmcl.2023.129143

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In our continuing efforts to explore structure-activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2-pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.

引用

页数：6

共 28 条

[1]

[Anonymous], THERE WAS LITTLE SEL

[2]

[Anonymous], The PyMOL Molecular Graphics System, Schrdinger

[3]

[Anonymous], THERE WERE NO HITS I

[4]

[Anonymous], SUPPLEMENTARY DATA D

[5]

[Anonymous], 15 ML VIAL WAS ADDED

[6] GSK-3 mouse models to study neuronal apoptosis and neurodegeneration [J].

Gomez-Sintes, Raquel ;

Hernandez, Felix ;

Lucas, Jose J. ;

Avila, Jesus .

FRONTIERS IN MOLECULAR NEUROSCIENCE, 2011, 4

[7] A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin [J].

Gray, Jhanelle E. ;

Infante, Jeffrey R. ;

Brail, Les H. ;

Simon, George R. ;

Cooksey, Jennifer F. ;

Jones, Suzanne F. ;

Farrington, Daphne L. ;

Yeo, Adeline ;

Jackson, Kimberley A. ;

Chow, Kay H. ;

Zamek-Gliszczynski, Maciej J. ;

Burris, Howard A., III .

INVESTIGATIONAL NEW DRUGS, 2015, 33 (06) :1187-1196

[8] The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents [J].

Griebel, Guy ;

Stemmelin, Jeanne ;

Lopez-Grancha, Mati ;

Boulay, Denis ;

Boquet, Gerald ;

Slowinski, Franck ;

Pichat, Philippe ;

Beeske, Sandra ;

Tanaka, Shinji ;

Mori, Akiko ;

Fujimura, Masatake ;

Eguchi, Junichi .

SCIENTIFIC REPORTS, 2019, 9 (1)

[9] The multifaceted roles of glycogen synthase kinase 3β in cellular signaling [J].

Grimes, CA ;

Jope, RS .

PROGRESS IN NEUROBIOLOGY, 2001, 65 (04) :391-426

[10]

Grundke-Iqbal I., 1986, J BIOL CHEM, V261, P6084

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