New inhibitors of steroid 11.beta.-hydroxylase. Structure-activity relation studies of metyrapone-like compounds

Abstract

A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11.beta.-hydroxylase [bovine adrenocortical mitochondria]. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-Pyridyl)propiophenone and .alpha.,.beta.-diphenyl-3-pyridineethanol were the most active new compounds. Each was 65% as potent as metyrapone. 3-Pyridyl-.alpha.-3-pyridylbenzyl ketone, 2-phenyl-2-(3-pyridyl)acetophenone, .alpha.-(diphenylmethyl)-3-pyridinemethanol and 1,2-di-3-pyridyl-1-propanol were 52, 32, 25 and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl-3-pyridyl ketone, benzyl-3-pyridyl ketone, 2-(3-pyridyl)acetophenone, 2-phenyl-1-(3-pyridyl)-1-propanone, .alpha.,.beta.-di-3-pyridylphenethyl alcohol and 1,2-di-3-pyridylethanol had < 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group .alpha. to the carbon bearing the O was necessary for appreciable activity. A 3-pyridyl group .alpha. to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group. [Selective inhibition of specific hydroxylases could conceivably result in willful control of adrenal steroid hormone output.].