Some 1-, and 3-substituted 3-(4'-aminophenyl)pyrrolidine-2,5-diones as selective inhibitors of aromatase.
1-Alkyl-3-(4'aminophenyl)pyrrolidine-2,5-diones (7,R = C3H7-C7H15) are potent inhibitors of aromatase in vitro, the 1-hexyl (Ki = 62nM) being about 100-fold more potent than aminoglutethimide (AG), and more selective in their ratio of aromatase:CSCC inhibitory potency. The 1-pentyl, 1-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. 1,3-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.
Whomsley
R
R
Welsh School of Pharmacy, University of Wales College of Cardiff.
Smith
H J
HJ
Nicholls
P J
PJ
Nazareth
W
W
Ahmadi
M
M
D000311:Adrenal Glands / Q000201:enzymology; D000616:Aminoglutethimide / Q000031:analogs & derivatives*; D000735:Androstenedione / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry*; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry*; D013739:Testosterone / Q000378:metabolism
D000814:Aniline Compounds; D047072:Aromatase Inhibitors; D013388:Succinimides; D000616:Aminoglutethimide; C082712:3-(4'-aminophenyl)pyrrolidine-2,5-dione; D013739:Testosterone; D000735:Androstenedione