Cofactor-specific modulation of 11beta-hydroxysteroid dehydrogenase 1 inhibitor potency.
11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta-hydroxysteroid dehydrogenase 1 inhibitors.
Sahni-Arya
Bhavana
B
Department of Chemical Enzymology, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, USA.
Flynn
Michael J
MJ
Bergeron
Laurie
L
Salyan
Mary Ellen K
ME
Pedicord
Donna L
DL
Golla
Rajasree
R
Ma
Zhengping
Z
Wang
Haixia
H
Seethala
Ramakrishna
R
Wu
Shung C
SC
Li
James J
JJ
Nayeem
Akbar
A
Gates
Cynthia
C
Hamann
Lawrence G
LG
Gordon
David A
DA
Blat
Yuval
Y
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009249:NADP / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
D011725:Pyridines; D013449:Sulfonamides; D014230:Triazoles; D009249:NADP; D042842:11-beta-Hydroxysteroid Dehydrogenases