- 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
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Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
- Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Blaser, Adrian,Conole, Daniel,Franzblau, Scott G.,Lotlikar, Manisha U.,Cooper, Christopher B.,Upton, Anna M.,Denny, William A.,Palmer, Brian D.
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supporting information
p. 1292 - 1307
(2019/02/25)
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- ANTIBACTERIAL COMPOUNDS AND USES THEREOF
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The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of tuberculosis.
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Paragraph 0099
(2017/09/28)
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- 3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00349
(2017/10/06)
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- AZEPANE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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PROBLEM TO BE SOLVED: To provide a compound that has 5-HT2C receptor agonist activity and is useful as a therapeutic agent or a preventive agent for stress urinary incontinence. SOLUTION: The present invention provides an azepane derivative represented by the following formula or a pharmaceutically acceptable acid addition salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPO&INPIT
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Paragraph 0034
(2017/04/28)
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- Photochemically generated bicyclic ortho-quinodimethanes: Photo- enolization of bicyclic aldehydes and ketones
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A photoenolization route to bicyclic ortho-quinodimethanes was investigated. Bicyclic photoenols were trapped in an intermolecular fashion with various dienophiles for the first time. All ortho-quinodimethane precursors were prepared via a selective route commencing with 1-indanol, α- tetralol and 1-benzosuberone. Irradiation afforded the E-photoenols exclusively which were trapped with equal efficiency except that derived from indane-4-carboxaldehyde. This low efficiency has been ascribed to rapid auto- oxidation of the aldehyde to carboxylic acid. The facial selectivity of the reaction between the photoenol from benzosuberan-9-carboxaldehyde and dimethyl fumarate was much lower when compared to the other aldehydes in this study. A distorted diene caused by the presence of the seven membered ring explains these results.
- Connolly, Terrence J.,Durst, Tony
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p. 15969 - 15982
(2007/10/03)
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- ACYLATED AMINO ACIDS AS ENDOTHELIN ANTAGONISTS
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Novel acylated amino acids which are antagonists of endothelin are described. Methods for their preparation and pharmaceutical compositions containing them are also included. The compounds are expected to be useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, diabetes, head injury, and stroke.
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- SYNTHESIS OF TRICYCLIC BENZAZEPINES AND THEIR DOPAMINE D1- AND D2-AFFINITY
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A new group of angular 8,9-annelated 3-benzazepines has been found to be potent and selective dopamine D1-receptor antagonists of interest as possible pharmaceuticals in the treatment of schizophrenia.The synthesis of three new conformationally constrained representatives of this group of benzazepines is described and their affinity to the D1-receptor evaluated.Although none of these proved superior to the previously examined compounds, useful information on the receptor binding site was obtained.
- Horn Jensen, Eva,Nielsen, Per Halfdan
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p. 2441 - 2458
(2007/10/03)
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