385-02-4Relevant academic research and scientific papers
Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8
Padilla-Salinas, Rosaura,Anderson, Rachel,Sakaniwa, Kentaro,Zhang, Shuting,Nordeen, Patrick,Lu, Chuanjun,Shimizu, Toshiyuki,Yin, Hang
, p. 10221 - 10244 (2019/11/29)
Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.
INHIBITORS OF STEAROYL-COA DESATURASE
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, (2009/06/27)
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity.
AROMATIC AMIDES
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, (2008/06/13)
This application relates to a compound of formula I (or a pharmaceutically acceptable salt thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.
Antagonist, Partial Agonist, and Full Agonist Imidazoquinoxaline Amides and Carbamates Acting through the GABAA/benzodiazepine Receptor
TenBrink, Ruth E.,Im, Wha B.,Sethy, Vimala H.,Tang, Andrew H.,Carter, Don B.
, p. 758 - 768 (2007/10/02)
(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazopyrroloquinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazoquinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazopyrroloquinoxaline-1-carboxylate (1e), as well as other imidazoquinoxaline amides and carbamates, represent a new series of compounds which bind with high affinity to the GABAA/benzodiazepine receptor.These compound exhibit a wide range of intrinsic efficacies as measured by TBPS binding ratios.The synthesis of 1a begins with the addition of DL-glutamic acid to 1-fluoro-2-nitrobenzene, followed by reduction of the nitro group and subsequent ring closure to form 3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinoxalin-2-one, followed by a second ring closure to afford (4RS)-1,5-dioxo-1,2,3,4,5,6-hexahydropyrroloquinoxaline as the key intermediate.Appendage of a substituted imidazo ring via the anion of 5-cyclopropyl-1,2,4-oxadiazol-3-yl gives 1a.The (-) and (+)-isomers of 1a were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for flunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.
Imidazodiazepine derivatives
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, (2008/06/13)
Imidazodiazepine derivatives of the formula STR1 wherein A together with the two carbon atoms denoted as α and β is selected from the group consisting of STR2 the dotted line represents the double bond present in groups (a) and (b), D is >C O or >C S, R 1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR 4, R 4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R 5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R 6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R 2 is hydrogen and R 3 is hydrogen or lower alkyl or R 2 and R 3 together are trimethylene or propenylene and the carbon atom denoted as γ has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one.Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.
