- 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 101
(2021/12/31)
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- 2,2,3-Tribromopropanal as a versatile reagent in the skraup-type synthesis of 3-bromoquinolin-6-ols
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2,2,3-Tribromopropanal, a reagent which almost became forgotten in the chemical literature after its first application in the 1950s, is used for the one-step transformation of diversely substituted 4-nitro- and 4-methoxyanilines into 3-bromo-6-nitroquinolines and 3-bromo-6-methoxyquinolines. These intermediates are then converted, in one further step, into 3-bromoquinolin-6- ols, which may carry additional substituents at positions 7 and 8. Georg Thieme Verlag Stuttgart New York.
- Lamberth, Clemens,Kessabi, Fiona Murphy,Beaudegnies, Renaud,Quaranta, Laura,Trah, Stephan,Berthon, Guillaume,Cederbaum, Fredrik,Vettiger, Thomas,Prasanna
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p. 858 - 862
(2014/04/17)
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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 0702
(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; 0459
(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; 64
(2012/08/28)
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- QUINOLIN-, ISOQUINOLIN-, AND QUINAZOLIN-OXYALKYLAMIDES AND THEIR USE AS FUNGICIDES
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Fungicidal compounds of the general formula (1) wherein one of X and Y is N or N-oxide and the other is CR or both of X and Y are N.
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