Pyridine amides as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Wang
Haixia
H
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. haixia.wang@bms.com
Ruan
Zheming
Z
Li
James J
JJ
Simpkins
Ligaya M
LM
Smirk
Rebecca A
RA
Wu
Shung C
SC
Hutchins
Robert D
RD
Nirschl
David S
DS
Van Kirk
Katy
K
Cooper
Christopher B
CB
Sutton
James C
JC
Ma
Zhengping
Z
Golla
Rajasree
R
Seethala
Ramakrishna
R
Salyan
Mary Ellen K
ME
Nayeem
Akbar
A
Krystek
Stanley R
SR
Sheriff
Steven
S
Camac
Daniel M
DM
Morin
Paul E
PE
Carpenter
Brian
B
Robl
Jeffrey A
JA
Zahler
Robert
R
Gordon
David A
DA
Hamann
Lawrence G
LG
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D011725:Pyridines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1