1226773-35-8Relevant articles and documents
Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors
Moreno-Sanz, Guillermo,Duranti, Andrea,Melzig, Laurin,Fiorelli, Claudio,Ruda, Gian Filippo,Colombano, Giampiero,Mestichelli, Paola,Sanchini, Silvano,Tontini, Andrea,Mor, Marco,Bandiera, Tiziano,Scarpelli, Rita,Tarzia, Giorgio,Piomelli, Daniele
, p. 5917 - 5930 (2013/08/23)
The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3′-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3′-carbamoyl-5- hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.
Design, synthesis, and structure-activity relationship of trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents
Ding, Dazhong,Meng, Qingqing,Gao, Guangwei,Zhao, Yaxue,Wang, Qing,Nare, Bakela,Jacobs, Robert,Rock, Fernando,Alley, Michael R. K.,Plattner, Jacob J.,Chen, Guoqiang,Li, Dawei,Zhou, Huchen
, p. 1276 - 1287 (2011/05/07)
African trypanosomiasis, caused by the proto zoal pathogen Trypanosoma brucei (T. brucei), is one of the most neglected tropical diseases that are in great need of new drugs. We report the design and synthesis of T. brucei leucyl-tRNA synthetase (TbLeuRS) inhibitors and their structure-activity relationship. Benzoxaborole was used as the core structure and C(6) was modified to achieve improved affinity based on docking results that showed further binding space at this position. Indeed, compounds with C(7) substitutions showed diminished activity due to clash with the eukaryote specific I4ae helix while substitutions at C(6) gave enhanced affinity. TbLeuRS inhibitors with IC 50 as low as 1.6 μM were discovered, and the structure-activity relationship was discussed. The most potent enzyme inhibitors also showed excellent T. brucei parasite growth inhibition activity. This is the first time that TbLeuRS inhibitors are reported, and this study suggests that leucyl-tRNA synthetase (LeuRS) could be a potential target for antiparasitic drug development.
Discovery of novel benzoxaborole-based potent antitrypanosomal agents
Ding, Dazhong,Zhao, Yaxue,Meng, Qingqing,Xie, Dongsheng,Nare, Bakela,Chen, Daitao,Bacchi, Cyrus J.,Yarlett, Nigel,Zhang, Yong-Kang,Hernandez, Vincent,Xia, Yi,Freund, Yvonne,Abdulla, Maha,Ang, Kean-Hooi,Ratnam, Joseline,McKerrow, James H.,Jacobs, Robert T.,Zhou, Huchen,Plattner, Jacob J.
scheme or table, p. 165 - 169 (2010/10/21)
We report the discovery of benzoxaborole antitrypanosomal agents and their structure?activity relationships on central linkage groups and different substitution patterns in the sulfur-linked series. The compounds showed in vitro growth inhibition IC5
