Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11beta-hydroxysteroid dehydrogenase type 1 inhibitors.
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.
Rohde
Jeffrey J
JJ
Metabolic Disease Research, Abbott Laboratories, Department R4CB, Building AP52, Abbott Park, Illinois 60064-3500, USA. jeffrey.j.rhode@abbott.com
Pliushchev
Marina A
MA
Sorensen
Bryan K
BK
Wodka
Dariusz
D
Shuai
Qi
Q
Wang
Jiahong
J
Fung
Steven
S
Monzon
Katina M
KM
Chiou
William J
WJ
Pan
Liping
L
Deng
Xiaoqing
X
Chovan
Linda E
LE
Ramaiya
Atul
A
Mullally
Mark
M
Henry
Rodger F
RF
Stolarik
DeAnne F
DF
Imade
Hovis M
HM
Marsh
Kennan C
KC
Beno
David W A
DW
Fey
Thomas A
TA
Droz
Brian A
BA
Brune
Michael E
ME
Camp
Heidi S
HS
Sham
Hing L
HL
Frevert
Ernst Uli
EU
Jacobson
Peer B
PB
Link
J T
JT
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
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