251361-29-2Relevant academic research and scientific papers
4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger slc26a3 (Downregulated in Adenoma) for Anti-Absorptive Therapy of Constipation
Lee, Sujin,Cil, Onur,Haggie, Peter M.,Verkman, Alan S.
supporting information, p. 8330 - 8337 (2019/10/11)
The chloride/bicarbonate exchanger SLC26A3 (downregulated in adenoma) is expressed mainly in colonic epithelium, where it dehydrates the stool by facilitating the final step of chloride and fluid absorption. SLC26A3 inhibition has predicted efficacy in various types of constipation including that associated with cystic fibrosis. We previously identified, by high-throughput screening, 4,8-dimethylcoumarin inhibitors of murine slc26a3 with IC50 down to a150 nM. Here, we synthesized a focused library of forty-three 4,8-dimethylcoumarin analogues. Structure-activity studies revealed the requirement of 4,8-dimethylcoumarin-3-acetic acid for activity. The most potent inhibitors were produced by replacements at C7, including 3-iodo- (4az) and 3-trifluoromethyl- (4be), with IC50 of 40 and 25 nM, respectively. Pharmacokinetics in mice showed predicted therapeutic concentrations of 4az for >72 h following a single 10 mg/kg oral dose. 4az at 10 mg/kg fully normalized stool water content in a loperamide-induced mouse model of constipation. The favorable inhibition potency, selectivity within the SLC26 family, and pharmacological properties of 4az support its further preclinical development.
Nonpeptidic Selective Inhibitors of the Chymotrypsin-Like (β5 i) Subunit of the Immunoproteasome
Sosi?, Izidor,Gobec, Martina,Brus, Boris,Knez, Damijan,?ivec, Matej,Konc, Janez,Le?nik, Samo,Ogrizek, Mitja,Obreza, Ale?,?igon, Du?an,Jane?i?, Du?anka,Mlinari?-Ra??an, Irena,Gobec, Stanislav
supporting information, p. 5745 - 5748 (2016/05/09)
Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
PSORALEN DERIVATIVES AS NON-PEPTIDIC INHIBITORS OF CHYMOTRYPSIN-LIKE ACTIVITY OF THE IMMUNOPROTEASOME
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Paragraph 0215; 0216; 0217, (2016/10/11)
This invention relates to new inhibitors of chymothrypsin-like activity of the immunoproteasome (inhibitors of β5? or LMP7 subunit) with the general formula (I), where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of diseases where immunoproteasome activity is increased.
Coumarin-based inhibitors of bacillus anthracis and staphylococcus aureus replicative DNA helicase: Chemical optimization, biological evaluation, and antibacterial activities
Li, Bing,Pai, Ramdas,Di, Ming,Aiello, Daniel,Barnes, Marjorie H.,Butler, Michelle M.,Tashjian, Tommy F.,Peet, Norton P.,Bowlin, Terry L.,Moir, Donald T.
, p. 10896 - 10908 (2013/03/13)
The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial tar
Synthesis of modified psoralen analogues
Garazd,Garazd,Ogorodniichuk,Khilya
, p. 291 - 300 (2007/10/03)
Substituted 3-(5-methyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acids analogous to psoralen were synthesized by linear annulation of a furan moiety to the coumarin system.
Synthesis and biological evaluation of coumarincarboxylic acids as inhibitors of gyrase B. L-rhamnose as an effective substitute for L-noviose
Ferroud, Didier,Collard, Jeannine,Klich, Michel,Dupuis-Hamelin, Claudine,Mauvais, Pascale,Lassaigne, Patrice,Bonnefoy, Alain,Musicki, Branislav
, p. 2881 - 2886 (2007/10/03)
A series of novobiocin-like coumarincarboxylic acids has been prepared bearing the L-rhamnosyl moiety as the sugar portion of the molecule. The similar DNA gyrase inhibitory activity of the novel class of coumarins to that of novobiocin demonstrates that L-rhamnose can effectively replace L-novoise. Introduction of alkyl side-chains at C-5 of coumarin leads to improved in vitro antibacterial properties in the novel series.
