title: New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues.
abstract: Derivatives of etomidate were evaluated as inhibitors of adrenal steroid 11beta-hydroxylations. Stereoselective coupling by Mitsunobu produced chirally pure analogues to study the effect of configuration, modification of the ester, and substitution in the phenyl ring, with the aim to probe specific sites for introducing a radionuclide. Iodophenyl metomidate (IMTO) labeled with iodine-131 served as radioligand for structure-affinity relationship studies. We have characterized the kinetic parameters of specific (131)I-IMTO binding on rat adrenal membranes and used the displacement of (131)I-IMTO binding to evaluate functionalized MTO analogues. Our results indicated that (1) ( R)-configuration is essential for high affinity, (2) highest potency resides in the ethyl, 2-propyl, and 2-fluoroethyl esters, and (3) substitution of the phenyl ring is well tolerated. The clinically used inhibitors metyrapone and ketoconazole inhibited (131)I-IMTO binding with low affinity. Incubation of selected analogues with human adrenocortical NCI-h295 cells demonstrated a high correlation with the inhibitory effect on cortisol secretion.
authors.affiliation: Department of Medicinal/Pharmaceutical Chemistry and Institute of Organic Chemistry, University of Vienna, Vienna, Austria. ilse.zolle@univie.ac.at
authors.forename: Ilse M
authors.initials: IM
authors.lastname: Zolle
authors.forename: Michael L
authors.initials: ML
authors.lastname: Berger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Hammerschmidt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahner
authors.forename: Andreas
authors.initials: A
authors.lastname: Schirbel
authors.forename: Biljana
authors.initials: B
authors.lastname: Peric-Simov
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D005045:Etomidate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007457:Iodine Radioisotopes / Q000737:chemistry; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007457:Iodine Radioisotopes; C529450:iodophenyl metomidate; D013252:Steroid 11-beta-Hydroxylase; D005045:Etomidate