397274-64-5Relevant articles and documents
Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety
Cohen, Frederick,Aggen, James B.,Andrews, Logan D.,Assar, Zahra,Boggs, Jen,Choi, Taylor,Dozzo, Paola,Easterday, Ashton N.,Haglund, Cat M.,Hildebrandt, Darin J.,Holt, Melissa C.,Joly, Kristin,Jubb, Adrian,Kamal, Zeeshan,Kane, Timothy R.,Konradi, Andrei W.,Krause, Kevin M.,Linsell, Martin S.,Machajewski, Timothy D.,Miroshnikova, Olga,Moser, Heinz E.,Nieto, Vincent,Phan, Thu,Plato, Craig,Serio, Alisa W.,Seroogy, Julie,Shakhmin, Anton,Stein, Adam J.,Sun, Alex D.,Sviridov, Serguei,Wang, Zhan,Wlasichuk, Kenneth,Yang, Wen,Zhou, Xiaoming,Zhu, Hai,Cirz, Ryan T.
, p. 1560 - 1572 (2019/08/16)
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL?1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
ANTIBACTERIAL AGENTS
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Page/Page column 104, (2013/12/03)
Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
56. Unusual and Novel C11H16 Hydrocarbons from the Southern Australian Brown Alga Dictyopteris acrostichoides (Phaeophyceae)
Wirth, Dieter,Fischer-Lui, Iris,Boland, Wilhelm,Icheln, Detlef,Runge, Thorsten,et al.
, p. 734 - 744 (2007/10/02)
Unusual and novel C11H16 olefins with (E)- or (E,E)-configuration instead of the previously known (Z)- or (E,Z)-configuration at the double bond(s) within the longer side chain are the main products of the Australian phaeophyte Dictyopteris acrostichoides.This configuration anomaly refers to all four series of alicyclic C11H16 hydrocarbons, namely the disubstituted cyclopentenes and cyclopropanes, as well as the monosubstituted cycloheptadienes and cyclopentenes.Chiral compounds within the above series have the same absolute configuration.The two (cyclopent-3-enyl)hexa-1,3-dienes 11 and 13 are found for the first time.The absolute configuration and optical purity of the hydrocarbons are determined by gas chromatography on modified cyclodextrins as chiral stationary phases.The synthesis of chiral references via lipase-catalyzed resolutions is described.
