17744-02-4Relevant academic research and scientific papers
PYRIDAZINONE DERIVATIVES AND USE THEREOF AS P2X7 RECEPTOR INHIBITORS
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Page/Page column 158, (2009/06/27)
Novel pyridazinone compounds of formula (I), which inhibit the purinergic P2X7 receptor and are useful for prevention, therapy and improvement of inflammatory and immunological diseases.
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.
