title: Interference of C17-spirosteroids with late steps of aldosterone biosynthesis. Structure-activity studies.
abstract: Structure-activity relationships concerning the steroidal skeleton as well as the C21,17-ring systems could be established while investigating the inhibitory effects of 27 different C17-spirosteroids on aldosterone synthesis in vitro. 18-hydroxylation appeared to be the crucial point of interference with all active compounds, whereas impairment of 11 beta- and 21-hydroxylase, respectively, was of minor importance, i.e. occurring to a smaller degree and only with a few test substances. Inhibition of 18-hydroxylation was associated with the following structural features: C21,17-spiro-gamma-lactone ring with 17 beta-O-atom; 3-oxo group in combination with delta 4,5-6,7-diene structure or, alternately, combination of 3-oxo group or even a bulky 3-O-function, if it protrudes out of ring plane in beta-position, and 7a-thioalkyl- or thioacyl- or thiol groups; combination of 17-spiro-gamma-lactone and a 3-O-function may result in an active compound even without 7a-substituents, provided there are no additional groups fixed on the steroidal skeleton. Elimination of an angular methyl group (----nor-compound), however, is acceptable. On the other hand, inhibitory potency is abolished or diminished by the following structural features: 7a-groups containing oxidized sulphur (e.g. suphoxy- or sulphonyl groups); bulky 3-substituents fixed in the ring plane via double bond; 18-alkyl groups; 6 beta-substituents; 2-substituents in absence of 7a-groups, depending on their configuration (e.g. cycle or chain); introduction of a heteroatom at C21, i.e. instead of the carbonyl-C-atom. Mespirenone (CAS 87952-98-5), the test substance of central concern, possesses favourable structural features finding its expression in a correspondingly enhanced inhibitory action.
authors.affiliation: Department of Pharmacology, University of Heidelberg, Fed. Rep. of Germany.
authors.forename: K
authors.initials: K
authors.lastname: Weindel
authors.forename: S
authors.initials: S
authors.lastname: Lewicka
authors.forename: P
authors.initials: P
authors.lastname: Vecsei
mesh_terms: D019326:17-alpha-Hydroxyprogesterone; D015069:18-Hydroxycorticosterone / Q000378:metabolism; D000450:Aldosterone / Q000031:analogs & derivatives / Q000096:biosynthesis*; D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis; D003864:Depression, Chemical; D006908:Hydroxyprogesterones / Q000378:metabolism; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D006908:Hydroxyprogesterones; D013148:Spironolactone; C032486:21-deoxyaldosterone; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D019326:17-alpha-Hydroxyprogesterone; D003345:Corticosterone