14483-74-0Relevant academic research and scientific papers
Effect of heterocycle content on metal binding isostere coordination
Cohen, Seth M.,Dick, Benjamin L.,Patel, Ashay
, p. 6907 - 6914 (2020)
Bioisostere replacement is a core concept in modern medicinal chemistry and has proven an invaluable strategy to address pharmacodynamic and pharmacokinetic limitations of therapeutics. The success of bioisostere replacement is often dependent on the scaffold that is being modified (i.e., "context dependence"). The application of bioisostere replacement to a picolinic acid fragment was recently demonstrated as a means to expand a library of metal-binding pharmacophores (MBPs) to modulate their physicochemical properties, while retaining their metal binding and metalloenzyme inhibitory activity. Here, metal binding isosteres (MBIs) with different nitrogen-containing heteroarenes is explored. This resulted in a number of new MBIs that were evaluated for their physicochemical properties and metal binding features. It was observed that the coordination behavior of an MBI is dependent on the identity and arrangement of the heteroatoms within each heteroarene. To further understand the observed coordination chemistry trends, density functional theory (DFT) calculations were performed. Theory indicates that preferences in coordination geometry are largely determined by the electronic character of the heteroarene scaffold. These results provide important insights into the development of novel MBI scaffolds that can serve to broaden the scope of scaffolds for metalloenzyme inhibitor development.
Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl] piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors
Ontoria, Jesus M.,Bufi, Laura Llauger,Torrisi, Caterina,Bresciani, Alberto,Giomini, Claudia,Rowley, Michael,Serafini, Sergio,Bin, Hu,Hao, Wu,Steinkühler, Christian,Jones, Philip
scheme or table, p. 5274 - 5282 (2011/10/02)
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
The Cycloaddition Reactions of Benzimidazole-2-carbonitrile Oxide with Alkenes
Cundy, Darren J.,Simpson, Gregory W.
, p. 199 - 204 (2007/10/03)
Benzimidazole-2-carbonitrile oxide was prepared in situ and reacted with vinyl acetate, acrylonitrile, styrene, phenyl vinyl sulfone and 3,3,3-trifluoropropene to afford 2-(5'-acetoxyisoxazolin-3'-yl)-, 2-(5'-cyanoisoxazolin-3'-yl)-, 2,-(5'-phenylisoxazol
