76228-06-3Relevant articles and documents
NOVEL SUBSTITUTED TETRAHYDROQUINOLIN COMPOUNDS AS INDOLEAMINE 2,3-DIOXYGENASE (IDO) INHIBITORS
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, (2019/05/22)
Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof (I). Also disclosed herein are uses of the compounds disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities
Harland, Aubrie A.,Yeomans, Larisa,Griggs, Nicholas W.,Anand, Jessica P.,Pogozheva, Irina D.,Jutkiewicz, Emily M.,Traynor, John R.,Mosberg, Henry I.
, p. 8952 - 8969 (2015/12/09)
In a previously described peptidomimetic series, we reported the development of bifunctional δ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the δ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks
Song, Jiangli,Jones, Lindsay M.,Chavarria, Gustavo E.,Charlton-Sevcik, Amanda K.,Jantz, Adam,Johansen, Audra,Bayeh, Liela,Soeung, Victoria,Snyder, Lindsey K.,Lade Jr., Shawn D.,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
, p. 2801 - 2807 (2013/06/27)
Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl-alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure-activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC50 50 = 164 nM. All of the compounds evaluated were inactive (IC50 >10,000 nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.