26054-60-4Relevant articles and documents
MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS
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Page/Page column 38, (2010/04/30)
The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.
N-HYDROXYAMIDE DERIVATIVES POSSESSING ANTIBACTERIAL ACTIVITY
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Page/Page column 49-50, (2010/02/17)
Described herein are N-hydroxyamlde antibacterial compounds, methods for making the compounds, pharmaceutical compositions containing the compounds and methods of treating bacterial infections utilizing the compounds and pharmaceutical compositions compound of Formula (I): or a salt, solvate ti hydrate thereof, wherein A is (a) eachindicates a point of attachment.
Synthesis of (2S)-2-amino-7,8-epoxyoctanoic acid and structure of its metal-bridging complex with human arginase i
Zakharian, Tatiana Y.,Di Costanzo, Luigi,Christianson, David W.
supporting information; experimental part, p. 3240 - 3243 (2009/02/05)
The synthesis of (2S)-2-amino-7,8-epoxyoctanoic acid is reported along with the X-ray crystal structure of its complex with human arginase I, revealing unique coordination interactions with two manganese ions in the enzyme active site. This journal is
Substituted indoles
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, (2008/06/13)
Compounds of the formula I are suitable for preparing pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.
Serine and threonine β-lactones: A new class of hepatitis A virus 3C cysteine proteinase inhibitors
Lall, Manjinder S.,Ramtohul, Yeeman K.,James, Michael N.G.,Vederas, John C.
, p. 1536 - 1547 (2007/10/03)
Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and infectivity and represents a target for the development of antiviral drugs. A number of serine and threonine β-lactones were synthesized and tested against HAV 3C proteinase. The D-N-Cbz-serine β-lactone 5a displays competitive reversible inhibition with a Ki value of 1.50 × 10-6 M. Its enantiomer, L-N-Cbz-serine β-lactone 5b is an irreversible inactivator with kinact = 0.70 min-1, KI = 1.84 × 10-4 M and kinact/KI = 3800 M-1 min-1. Mass spectrometry and HMQC NMR studies using 13C-labeled 5b show that inactivation of the enzyme occurs by nucleophilic attack of the cysteine thiol (Cys-172) at the β-position of the oxetanone ring. Although the N-Cbz-serine β-lactones 5a and 5b display potent inhibition, other related analogues with an N-Cbz side chain, such as the five-membered ring homoserine γ-lactones 14a and 14b, the four-membered ring β-lactam 33, 2-methylene oxetane 34, cyclobutanone 36, and 3-azetidinone 39, fail to give significant inhibition of HAV 3C proteinase, thus demonstrating the importance of the β-lactone ring for binding.
Viracept (nelfinavir mesylate, AG1343): A potent, orally bioavailable inhibitor of HIV-1 protease
Kaldor, Stephen W.,Kalish, Vincent J.,Davies II, Jay F.,Shetty, Bhasker V.,Fritz, James E.,Appelt, Krzysztof,Burgess, Jeffrey A.,Campanale, Kristina M.,Chirgadze, Nickolay Y.,Clawson, David K.,Dressman, Bruce A.,Hatch, Steven D.,Khalil, Deborah A.,Kosa, Maha B.,Lubbehusen, Penny P.,Muesing, Mark A.,Patick, Amy K.,Reich, Siegfried H.,Su, Kenneth S.,Tatlock, John H.
, p. 3979 - 3985 (2007/10/03)
Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor
Synthesis of phosphinic acid transition state analogues for the reaction catalysed by kynureninase
Ross, Fiona C.,Botting, Nigel P.,Leeson, Paul D.
, p. 2643 - 2646 (2007/10/03)
The syntheses of phosphinic acid and methyL phospinate analogues of kynurenine, designed as transition state mimics for the enzyme kynureninase are described, along with their inhibitory properties.
A convenient, large scale synthesis of N-CBZ-(S-phenyl)-L-cysteine
Marzoni,Kaldor,Trippe,Shamblin,Fritz
, p. 2475 - 2482 (2007/10/02)
N-Cbz-(S-phenyl)-L-cysteine (3) has been prepared on a multikilogram scale in high yield and optical purity from the β-lactone of N-Cbz-L-serine.
Mechanism of formation of serine β-lactones by Mitsunobu cyclization: synthesis and use of L-serine stereospecifically labelled with deuterium at C-3
Ramer, Shawn E.,Moore, Richard N.,Vederas, John C.
, p. 706 - 713 (2007/10/02)
The ring closure of N-benzyloxycarbonyl-L-serine (1) under Mitsunobu conditions (Ph3P, dimethyl azodicarboxylate, -78 deg C) to give the corresponding β-lactone (2) is shown by deuterium and oxygen-18 labelling studies to proceed by hydroxy group activation, in contrast to analogous cyclizations of more hindered β-hydroxy acids, which usually occur by carboxy group activation.Samples of 1 stereospecifically labelled with deuterium at C-3 were prepared by hydrogenation of (Z)-2-acetamido-3-methoxyacrylic acid (9) with deuterium, followed by selective Acylase I deacetylation of the 2S isomer, removal of the protecting groups, and N-acylation of the resulting L-serine with benzyl chloroformate.Mitsunobu cyclizations of this 3R deuterated N-acyl serine, of the analog lg, and of the derivative 1f show that lactonization occurs with inversion of configuration at C-3, loss of the hydroxy oxygen, and retention of the carboxy oxygens.Similar labelling experiments demonstrate that aqueous sodium hydroxide opens the β-lactone ring by exclusive attack at the carbonyl to regenerate 1, whereas acidic hydrolysis proceeds primarily by attack of water at the C-3 methylene group of 2.This information allows interconversion of L-serines that are stereospecifically labelled at C-3 with hydrogen isotopes and affords access to other labelled β-substituted alanines.
