Discovery of adamantane ethers as inhibitors of 11beta-HSD-1: Synthesis and biological evaluation.
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
Patel
Jyoti R
JR
Global Pharmaceutical Research & Development, Abbott Laboratories, R43G, AP52, 200 Abbott Park Road, Abbott Park, IL-60064-6217, USA. jyoti.patel@abbott.com
Shuai
Qi
Q
Dinges
Jurgen
J
Winn
Marty
M
Pliushchev
Marina
M
Fung
Steven
S
Monzon
Katina
K
Chiou
William
W
Wang
Jiahong
J
Pan
Liping
L
Wagaw
Seble
S
Engstrom
Kenneth
K
Kerdesky
Francis A
FA
Longenecker
Kenton
K
Judge
Russell
R
Qin
Wenying
W
Imade
Hovis M
HM
Stolarik
Deanne
D
Beno
David W A
DW
Brune
Michael
M
Chovan
Linda E
LE
Sham
Hing L
HL
Jacobson
Peer
P
Link
J T
JT
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000478:Alkylation; D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D004987:Ethers; D007202:Indicators and Reagents; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane