Some 1-, and 3-Substituted 3-(4 - Aminophenyl)Pyrrolidine-2,5-Diones as Selective Inhibitors of Aromatase

Abstract

l-Alky1-3-(4′aminophenyl)pyrrolidine-2,5-diones (7,R = C₃H₇-C₇H₁₅) are potent inhibitors of aromatase in vitro, the l-hexyl (K; = 62nM) being about 100-fold more potent than aminoglutethimide (AG), and more selective in their ratio of aromatase:CSCC inhibitory potency. The 1-pentyl, l-hexyl and 1-heptyl derivatives are more stable to liver microsomal metabolism in vitro than AG possibly due to inhibition of the liver cytochrome P450s.

l,3-Dialkyl-3(4′-aminophenyl)pyrrolidine-2,5-diones (9) have been synthesised by a novel method. Although the higher homologues (di-pentyl and di-hexyl) are more potent in vitro as inhibitors of aromatase than AG. they are less active than their 1-alkyl counterparts with the same alkyl substituent.

Key Words: :

• Aromatase
• Inhibition
• 1-, and 3-substituted 3-(4′-aminophenyl)pyrrolidine-2,5-diones
• aminoglutethimide
• pyridoglutethimide