title: Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11beta-hydroxysteroid dehydrogenase type 1 inhibitors.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, Department R4CB, Building AP52, Abbott Park, Illinois 60064-3500, USA. jeffrey.j.rhode@abbott.com
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rohde
authors.forename: Marina A
authors.initials: MA
authors.lastname: Pliushchev
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Qi
authors.initials: Q
authors.lastname: Shuai
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Fung
authors.forename: Katina M
authors.initials: KM
authors.lastname: Monzon
authors.forename: William J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: Liping
authors.initials: L
authors.lastname: Pan
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Deng
authors.forename: Linda E
authors.initials: LE
authors.lastname: Chovan
authors.forename: Atul
authors.initials: A
authors.lastname: Ramaiya
authors.forename: Mark
authors.initials: M
authors.lastname: Mullally
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: DeAnne F
authors.initials: DF
authors.lastname: Stolarik
authors.forename: Hovis M
authors.initials: HM
authors.lastname: Imade
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fey
authors.forename: Brian A
authors.initials: BA
authors.lastname: Droz
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Ernst Uli
authors.initials: EU
authors.lastname: Frevert
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: J T
authors.initials: JT
authors.lastname: Link
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C517641:N-(5-hydroxy-2-adamantyl)-2(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionamide; C517640:N-(5-hydroxy-2-adamantyl)-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetamide; D010879:Piperazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane