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.
Yan
Xuelei
X
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. xueleiy@amgen.com
Wang
Zhulun
Z
Sudom
Athena
A
Cardozo
Mario
M
DeGraffenreid
Michael
M
Di
Yongmei
Y
Fan
Pingchen
P
He
Xiao
X
Jaen
Juan C
JC
Labelle
Marc
M
Liu
Jinsong
J
Ma
Ji
J
McMinn
Dustin
D
Miao
Shichang
S
Sun
Daqing
D
Tang
Liang
L
Tu
Hua
H
Ursu
Stefania
S
Walker
Nigel
N
Ye
Qiuping
Q
Powers
Jay P
JP
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