The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors.
In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. xueleiy@amgen.com
Xuelei
X
Yan
Zhulun
Z
Wang
Athena
A
Sudom
Mario
M
Cardozo
Michael
M
DeGraffenreid
Yongmei
Y
Di
Pingchen
P
Fan
Xiao
X
He
Juan C
JC
Jaen
Marc
M
Labelle
Jinsong
J
Liu
Ji
J
Ma
Dustin
D
McMinn
Shichang
S
Miao
Daqing
D
Sun
Liang
L
Tang
Hua
H
Tu
Stefania
S
Ursu
Nigel
N
Walker
Qiuping
Q
Ye
Jay P
JP
Powers
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D013450:Sulfones; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human