- Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity
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The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (μM) minimum inhibitory concentrations against wild-type uropathogenic Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. A 2.98 ? resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.
- Verma, Vishal A.,Wang, Lan,Labadie, Sharada S.,Liang, Jun,Sellers, Benjamin D.,Wang, Jian,Dong, Liting,Wang, Qiuyue,Zhang, Shuang,Xu, Zhongya,Zhang, Yexia,Niu, Yanan,Wang, Xinxin,Wai, John,Koehler, Michael F. T.,Hu, Huiyong,Alexander, Mary Kate,Nishiyama, Mireille,Miu, Anh,Xu, Yiming,Pang, Jodie,Katakam, Anand K.,Reichelt, Michael,Austin, Cary D.,Ho, Hoangdung,Payandeh, Jian,Koth, Christopher M.
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supporting information
p. 4085 - 4120
(2022/03/02)
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- 2'-(QUINOLIN-3-YL)-5',6'-DIHYDROSPIRO[AZETIDINE-3,4'-PYRROLO[1,2-B]PYRAZOLE]-1-CARBOXYLATE DERIVATIVES AND RELATED COMPOUNDS AS MAP4K1 (HPK1) INHIBITORS FOR THE TREATMENT OF CANCER
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The present invention relates to Map4K1 inhibitors of formula (I), to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, respectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients. The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
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Page/Page column 100
(2021/12/31)
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- SUBSTITUTED 1,5-NAPHTHYRIDINES OR QUINOLINES AS ALK5 INHIBITORS
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The present disclosure provides inhibitors of activin receptor-like kinase 5 (ALK5). Also disclosed are methods to modulate the activity of ALK5 and methods of treatment of disorders mediated by ALK5.
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Paragraph 410; 411
(2021/05/29)
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- ALK5 INHIBITORS
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The present disclosure provides inhibitors of activin receptor-like kinase 5 (ALK5). Also disclosed are methods to modulate the activity of ALK5 and methods of treatment of disorders mediated by ALK5.
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Paragraph 0917; 0918
(2020/07/07)
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- SHP2 PHOSPHATASE INHIBITORS AND METHODS OF USE THEREOF
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The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.
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Paragraph 0229
(2019/10/15)
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- Quinoline compounds and preparation method thereof, and intermediate, pharmaceutical composition and application of quinoline compounds
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The invention discloses quinoline compounds and a preparation method thereof, and an intermediate, a pharmaceutical composition and application of quinoline compounds. The invention provides quinoline compounds disclosed as Formula 1, and pharmaceutically acceptable salts, solvates, metabolites, metabolism precursors or pharmaceutical precursors thereof. The quinoline compounds have favorable inhibitory effects on tyrosine kinase C-Met, and can be used for preparing drugs for prevention, treatment or auxiliary treatment on multiple diseases related to C-Met expression or activity, and especially neoplastic diseases.
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Paragraph 0830-0832
(2018/02/04)
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- 6 - SUBSTITUTED 3 - (QUINOLIN- 6 - YLTHIO) - [1,2,4] TRIAZOLO [4, 3 -A] PYRADINES AS TYROSINE KINASE
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The invention relates to compounds of formula (I) and salts thereof: Formula (I) wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).
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Page/Page column 75
(2013/03/28)
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- TRIAZOLOPYRIDINE COMPOUNDS
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The invention relates to compounds of formula (I) and salts thereof: wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound o f formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I)
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Paragraph 0700
(2013/09/26)
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- [1,2,4] TRIAZOLO [4,3-B] PYRIDAZINE COMPOUNDS AS INHIBITORS OF THE C-MET TYROSINE KINASE
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The invention relates to compounds of formula (I) and salts thereof: wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).
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Paragraph 0456; 0457
(2014/01/07)
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- [1, 2, 4] TRIAZOLO [4, 3 -B] PYRIDAZINE COMPOUNDS AS INHIBITORS OF THE C-MET TYROSINE KINASE
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The invention relates to compounds of formula (I) and salts thereof: wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).
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Page/Page column 63
(2012/08/28)
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- BICYCLIC TRIAZOLES AS PROTEIN KINASE MODULATORS
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The present disclosure provides bicyclic triazole protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.
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Page/Page column 90
(2008/12/05)
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- HETEROCYCLIC KINASE MODULATORS
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The present disclosure provides heterocyclic protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.
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Page/Page column 119
(2009/01/20)
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- Synthesis and Esterolytic Activity of Catalytic Peptide Dendrimers
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Peptide dendrimers were prepared by solid-phase peptide synthesis. Monomeric dendrimers were first obtained by assembly of a hexa-peptide sequence containing alternate standard a-amino acids with diamino acids as branching units. The monomeric dendrimers were then dimerized by disulfide-bridge formation at the core cysteine. The synthetic strategy is compatible with functional amino acids and different diamino acid branching units. Peptide dendrimers composed of the catalytic triad amino acids histidine, aspartate, and serine catalyzed the hydrolysis of N-methylquinolinium salts when the histidine residues were placed at the outermost position. The dendrimer-catalyzed hydrolysis of 7-isobutyryl-N-methylquinolinium followed saturation kinetics with a rate constant of catalysis/rate constant without catalysis (kcat/kuncat) value of 3350 and a rate constant of catalysis/Michaelis constant (kcat/KM) value 350-fold larger than the second-order rate constant of the 4-methylimidazole-catalyzed reaction; this corresponds to a 40-fold rate enhancement per histidine side chain. Catalysis can be attributed to the presence of histidine residues at the surface of the dendrimers.
- Lagnonx, David,Delort, Estelle,Douat-Casassus, Celine,Esposito, Annamaria,Reymond, Jean-Louis
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p. 1215 - 1226
(2007/10/03)
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