Structural studies of metyrapone: a potent inhibitor of cytochrome P-450.

The crystal and molecular structure of metyrapone, a powerful inhibitor of certain cytochromes P-450, is described. Cytochrome P-450 enzymes are involved in metabolic processes, including those activating insecticides, drugs, and carcinogens. Metyrapone inhibits both the adrenal cytochrome P-450 catalyzing 11-beta-hydroxylation in steroid biosynthesis and most microsomal cytochromes P-450 induced by phenobarbital pretreatment. Crystal data are as follows: a = 11.828 (1), b = 6.268 (6), c = 18.269 (3) A, beta = 115.27 (1) degree, V = 1224.9 (3) A3, space group P21/c, dcalcd = 1.227 g cm-3, Z = 4. No intermolecular interactions are apparent in the solid state other than van der Waals forces. The torsion angle about the C(7)-C(10) bond to which the two 3-pyridyl groups are attached is 59.4 (1) degree. The three negatively charged heteroatoms form a triangle; the nitrogen atoms are anti to the exocyclic oxygen and are 4.347 (1) A apart. The N5-O11 distance is 5.850 (1) A; the N14-O11 intramolecular distance is 4.750 (1) A. The "twisted butterfly" conformation found for metyrapone is found in other molecules that are substrates and inducers of the specific cytochrome P-450 inhibited by metyrapone. The availability of nucleophilic functional groups is a feature common to most directly acting inhibitors of cytochrome P-450 enzymes and is manifested in metyrapone by the presence of the basic nitrogens. These factors may be necessary for interaction with the protein.