Interference of C17-spirosteroids with late steps of aldosterone biosynthesis. Structure-activity studies

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.