Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).
High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. daqings@amgen.com
Daqing
D
Sun
Zhulun
Z
Wang
Yongmei
Y
Di
Juan C
JC
Jaen
Marc
M
Labelle
Ji
J
Ma
Shichang
S
Miao
Athena
A
Sudom
Liang
L
Tang
Craig S
CS
Tomooka
Hua
H
Tu
Stefania
S
Ursu
Nigel
N
Walker
Xuelei
X
Yan
Qiuping
Q
Ye
Jay P
JP
Powers
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010879:Piperazines; D054852:Small Molecule Libraries; D013438:Sulfhydryl Compounds; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1