72116-06-4Relevant academic research and scientific papers
5-Phenyl-1,3,4-oxadiazol-2(3 H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit
Mahy, William,Willis, Nicky J.,Zhao, Yuguang,Woodward, Hannah L.,Svensson, Fredrik,Sipthorp, James,Vecchia, Luca,Ruza, Reinis R.,Hillier, James,Kj?r, Svend,Frew, Sarah,Monaghan, Amy,Bictash, Magda,Salinas, Patricia C.,Whiting, Paul,Vincent, Jean-Paul,Jones, E. Yvonne,Fish, Paul V.
, p. 12942 - 12956 (2020/11/13)
Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-Triazole 7 as an attractive starting point for a structure-based drug design hit-To-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.
Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity
Koksal, Meric,Ozkan-Dagliyan, Irem,Ozyazici, Tugce,Kadioglu, Beril,Sipahi, Hande,Bozkurt, Ayhan,Bilge, Suleyman S.
, (2017/09/05)
Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group exis
5-(3,4-dichlorophenyl)-3-{[4-(2-pyridyl)piperazine-1-yl]methyl}-1,3, 4-oxadiazole-2(3H)-one: Synthesis, characterization, X-ray and DFT structures
Sahin,Oezkan,Koeksal,Isik
, p. 938 - 942 (2013/04/23)
5-(3,4-Dichlorophenyl)-3-{[4-(2-pyridyl)piperazine-1-yl)]methyl}-1,3, 4-oxadiazole-2(3H)-one C18H17Cl2N 5O2 (3) is synthesized and characterized by IR, 1H NMR, 13C NMR, elemental
3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3, 4-oxadiazol-2(3H)-one, BMS-191011: Opener of large-conductance Ca 2+-activated potassium (maxi-K) channels, identification, solubility, and SAR
Romine, Jeffrey L.,Martin, Scott W.,Meanwell, Nicholas A.,Gribkoff, Valentin K.,Boissard, Christopher G.,Dworetzky, Steven I.,Natale, Joanne,Moon, Sandra,Ortiz, Astrid,Yeleswaram, Swamy,Pajor, Lorraine,Gao, Qi,Starrett Jr., John E.
, p. 528 - 542 (2007/10/03)
Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.
