- Synthetic studies to help elucidate the metabolism of the preclinical candidate TBAJ-876—a less toxic and more potent analogue of bedaquiline
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Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
- Choi, Peter J.,Conole, Daniel,Sutherland, Hamish S.,Blaser, Adrian,Tong, Amy S.T.,Cooper, Christopher B.,Upton, Anna M.,Palmer, Brian D.,Denny, William A.
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- PEPTIDOMIMETIC N5-METHYL-N2-(NONANOYL-L-LEUCYL)-L-GLUTAMINATE DERIVATIVES, TRIAZASPIRO[4.14]NONADECANE DERIVATIVES AND SIMILAR COMPOUNDS AS INHIBITORS OF NOROVIRUS AND CORONAVIRUS REPLICATION
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Peptidomimetic N5-methyl-N2-(nonanoyl-L-leucyl)-L-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds for use in methods of inhibiting the replication of noroviruses and coronaviruses in a biological sample or patient, for use in reducing the amount of noroviruses or coronaviruses in a biological sample or patient, and for use in treating norovirus and coronavirus in a patient, comprising administering to said biological sample or patient a safe and effective amount of a compound represented by formulae I or II, or a pharmaceutically acceptable salt thereof. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. page 99 to page 271; examples 1 to 3; compounds A1 to A104 and Bl to B66; tables A to E).
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Paragraph 00215; 00246
(2021/09/26)
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- METALLOENZYME INHIBITOR COMPOUNDS
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Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
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Page/Page column 301
(2018/09/28)
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- Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups
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Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols and phenols are generally converted into the corresponding primary sulfamates (ROSO2NH 2 and ArOSO2NH2, respectively) by reaction with sulfamoyl chloride (H2NSO2Cl). The lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine (e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates were further manipulated through reactions at the aryl substituent and finally deprotected with trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly attractive because deprotection occurred quantitatively within 2 h at room temperature with 10% trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine and deprotection] all proceeded in very high yields.
- Reuillon, Tristan,Bertoli, Annalisa,Griffin, Roger J.,Miller, Duncan C.,Golding, Bernard T.
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p. 7610 - 7617
(2012/10/29)
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- SODIUM CHANNEL INHIBITORS
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Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-gated sodium channels. More particularly, the invention provides substituted sulfonamides, composition
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Page/Page column 44
(2009/02/11)
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- Synthesis of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A2A receptor antagonists
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The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A2A receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were
- Cole, Andrew G.,Stauffer, Tara M.,Rokosz, Laura L.,Metzger, Axel,Dillard, Lawrence W.,Zeng, Wenguang,Henderson, Ian
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scheme or table
p. 378 - 381
(2011/03/18)
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- PYRROLE COMPOUNDS
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The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity, which is represented by the formula (I) wherein R1 is an optionally substituted cyclic group, R2 is a substituent, R3 is an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a halogen atom, a cyano group or a nitro group, R4 and R5 are each a hydrogen atom, an optionally substituted alkyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, a halogen atom, a cyano group or a nitro group, R6 and R6' are each a hydrogen atom or an alkyl group, and n is an integer of 0 - 3, or a salt thereof.
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Page/Page column 103-104
(2008/12/08)
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- A new route to secondary amines from bis-(alkoxymethyl)-alkylamines - The activation of an aminomethyl group and protection of the product by the same functional group
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Treatment of N,N-bis(alkoxymethyl)alkylamines with a variety of acidic reagents affords good yields of N-alkoxymethyl-N-alkylmethyleneiminium salts which react with trimethylsilyl enol ethers, and nucleophilic aromatic substrates to form protected secondary amines or tertiary amines by domino reactions; silyl ketene acetals afford tertiary amines only.
- Earle, Martyn J.,Fairhurst, Robin A.,Heaney, Harry,Papageorgiou, George,Wilkins, Robert F.
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p. 4229 - 4232
(2007/10/02)
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