- Functionalised bicyclic tetramates derived from cysteine as antibacterial agents
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Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.
- Panduwawala, Tharindi D.,Iqbal, Sarosh,Thompson, Amber L.,Genov, Miroslav,Pretsch, Alexander,Pretsch, Dagmar,Liu, Shuang,Ebright, Richard H.,Howells, Alison,Maxwell, Anthony,Moloney, Mark G.
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supporting information
p. 5615 - 5632
(2019/06/13)
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- Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
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Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- Hansen, Anders H?jgaard,Sergeev, Eugenia,Bolognini, Daniele,Sprenger, Richard R.,Ekberg, Jeppe Hvidtfeldt,Ejsing, Christer S.,McKenzie, Christine J.,Rexen Ulven, Elisabeth,Milligan, Graeme,Ulven, Trond
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p. 9534 - 9550
(2018/10/24)
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- (Substituted)acyl dipeptidyl inhibitors of the ICE/ced-3 family of cysteine proteases
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This invention is directed to novel (substituted)acyl dipeptidyl ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as the use of such compositions in the treatment of pa
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- Diels-Alder reactions of 2-azadienes derived from cysteine and serine methyl esters and aldehydes
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The Diels-Alder reactions of N-benzylidenedehydroalanine methyl ester 1a with but-3-en-2-one and with other electron deficient dienophiles have been found to give new dihydro- and tetrahydropyridines. The cycloaddition reactions are regioselective but not
- Gilchrist,Gilchrist, Thomas L.,Rocha Gonsalves D'A.,RochaGonsalves, Antonio M. D'A.,Pinho Melo,PinboMelo, Teresa M. V. D.
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p. 13709 - 13724
(2007/10/02)
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- CONVENIENT SYNTHESIS OF 1-AZA-3-THIABICYCLOHEXANES FROM L-CYSTEINE
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Synthesis of optically active 2-substituted and unsubstituted 1-aza-3-thiabicyclohexanes are accomplished by intramolecular cyclization of 4-hydroxymethylthiazolidine which are prepared by the reaction of L-cysteine methyl ester with appropriate aldehydes followed by reduction of ester function.
- Takata, Toshikazu,Kuo, Mingjung,Tamura, Yoshiharu,Kabe, Yoshio,Ando, Wataru
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p. 939 - 942
(2007/10/02)
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