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 J T
Metabolic Disease Research, Abbott Laboratories, Department R4CB, Building AP52, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 2007 Jan 11;50(1):149-64. doi: 10.1021/jm0609364.
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-HSD1 and are selective over 11beta-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 11beta-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 11beta-HSD1 inhibitors has been discovered.
从一种快速代谢的1型金刚烷11β-羟基类固醇脱氢酶（11β-HSD1）抑制剂22a出发，发现了一系列E-5-羟基-2-金刚烷胺抑制剂，以22d和（±）-22f为代表。与其他报道的物种选择性系列不同，这些化合物中的许多都是11β-HSD1的有效抑制剂，并且对多种物种（人、小鼠和大鼠）的11β-HSD2具有选择性。这些化合物具有良好的细胞活性和改善的微粒体稳定性。在啮齿动物中的药代动力学分析表明，分布容积中等至较大，半衰期短，并且存在药代动力学物种差异，在大鼠中用22d测量时暴露量最大。在小鼠离体试验中，用（±）-22f证实了给药后1小时肝脏、脂肪和脑组织中的11β-HSD1抑制作用。尽管5,7-二取代-2-金刚烷胺具有更高的稳定性，但单个E-5位极性官能团提供了具有稳定性、活性和选择性最佳组合的抑制剂。这些结果表明，已经发现了足以获得短效、强效和选择性11β-HSD1抑制剂的金刚烷代谢稳定作用。
