5854-75-1Relevant articles and documents
Synthesis of noradamantane derivatives by ring-contraction of the adamantane framework
Zonker, Benjamin,Becker, Jonathan,Hrdina, Radim
supporting information, p. 4027 - 4031 (2021/05/19)
We describe a triflic acid promoted cascade reaction of adamantane derivatives consisting of a decarboxylation of N-methyl protected cyclic carbamates and a subsequent intramolecular nucleophilic 1,2-alkyl shift to generate ring contracted iminium triflates. This reaction expands the family of similar transformations, such as Wagner-Meerwein-, Demjanov-Tiffeneau-, Meinwald- or (semi-)pinacol-rearrangement. It allows the preparation of noradamantane derivatives in a few steps, starting from simple hydroxy-substituted adamantane precursors.
Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1
Bach, Anders,Stuhr-Hansen, Nicolai,Thorsen, Thor S.,Bork, Nicolai,Moreira, Irina S.,Frydenvang, Karla,Padrah, Shahrokh,Christensen, S. Brogger,Madsen, Kenneth L.,Weinstein, Harel,Gether, Ulrik,Stromgaard, Kristian
scheme or table, p. 4281 - 4288 (2010/11/05)
Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with Cα-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-activity relationships of 1 by introducing subtle modifications of the acryloylcarbamate scaffold and variations of the substituents on this scaffold. The configuration around the double bond of 1 and analogues was settled by a combination of X-ray crystallography, NMR and density functional theory calculations. Thereby, docking studies were used to correlate biological affinities with structural considerations for ligand-protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK1 inhibition.
Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11β-hydroxysteroid dehydrogenase type 1 inhibitors
Rohde, Jeffrey J.,Pliushchev, Marina A.,Sorensen, Bryan K.,Wodka, Dariusz,Shuai, Qi,Wang, Jiahong,Fung, Steven,Monzon, Katina M.,Chiou, William J.,Pan, Liping,Deng, Xiaoqing,Chovan, Linda E.,Ramaiya, Atul,Mullally, Mark,Henry, Rodger F.,Stolarik, DeAnne F.,Imade, Hovis M.,Marsh, Kennan C.,Beno, David W. A.,Fey, Thomas A.,Droz, Brian A.,Brune, Michael E.,Camp, Heidi S.,Sham, Hing L.,Frevert, Ernst Uli,Jacobson, Peer B.,Link
, p. 149 - 164 (2008/02/01)
Starting from a rapidly metabolized adamantane 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (±)-22f, was discovered. Many of these compounds are potent inhibitors of 11β-HSD1 and are selective over 11β-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11β-HSD1 inhibition was confirmed with (±)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11β-HSD1 inhibitors has been discovered.
