60494-73-7Relevant articles and documents
Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1
Partridge, Katherine M.,Antonysamy, Stephen,Bhattachar, Shobha N.,Chandrasekhar, Srinivasan,Fisher, Matthew J.,Fretland, Adrian,Gooding, Karen,Harvey, Anita,Hughes, Norman E.,Kuklish, Steven L.,Luz, John G.,Manninen, Peter R.,McGee, James E.,Mudra, Daniel R.,Navarro, Antonio,Norman, Bryan H.,Quimby, Steven J.,Schiffler, Matthew A.,Sloan, Ashley V.,Warshawsky, Alan M.,Weller, Jennifer M.,York, Jeremy S.,Yu, Xiao-Peng
, p. 1478 - 1483 (2017)
We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80of 24 nM for inhibition of PGE2formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours.
Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine
Hirano, Tomoya,Fujiwara, Takashi,Niwa, Hideaki,Hirano, Michitake,Ohira, Kasumi,Okazaki, Yusuke,Sato, Shin,Umehara, Takashi,Maemoto, Yuki,Ito, Akihiro,Yoshida, Minoru,Kagechika, Hiroyuki
, p. 1530 - 1540 (2018/08/01)
The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2-hydroxy group showed the most potent activity. On the other hand, a 3-hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2-hydroxycyproheptadine. These results are expected to be helpful for further structure-based development of SET7/9 inhibitors.
PHENYLCARBOXYLIC ACID DERIVATIVES AND USE THEREOF FOR THE TREATMENT OF DIABETES
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Page/Page column 65-66, (2010/02/15)
The invention relates to compounds of general formula (1): in which R1, R2, R3, R4, R5, A, B, D and E are as defined in Claim 1, and also to the preparation process therefor and the therapeutic use thereof. These compounds can be used in the treatment of pathologies associated with hyperglycaemia.
