Some aryl substituted 2-(4-nitrophenyl)-4-oxo-4-phenylbutanoates and 3-(4-nitrophenyl)-1-phenyl-1,4-butanediols and related compounds as inhibitors of rat liver microsomal retinoic acid metabolising enzymes.
Some aryl substituted methyl 2-(4-nitrophenyl)-4-oxo-4-phenylbutanoates generally had poor to moderate inhibitory potency (4-73%) towards rat liver microsomal retinoic acid metabolising enzymes compared with ketoconazole (80%). Conversion to the corresponding 3-(4-nitrophenyl)-1-aryl-1,4-butanediols considerably increased potency (29-78%). The 4-iodophenyl analogue, (30) and the 4-iodo- (45) and 4-methoxyphenyl (46) analogues, were the most potent in both series respectively. The corresponding 5-membered lactones, in the three instances examined, were also potent (52%, 67%, 69%) as were the cis- and trans-isomers of the 5-membered tetrahydrofuran (77%, 65% respectively). Beckmann rearrangement of the oxime methyl 4-(2,4-dichlorophenyl)-4-hydroxyimino-2-(4-nitrophenyl)butanoate (54) gave the expected products (55) and (56), which were potent inhibitors (75%, 74% respectively) of the enzyme whereas the oxime was an activator.
Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff, CF10 3XF, UK.
Peter
P
Mason
Valerie P
VP
Greer
Andrew J
AJ
Kirby
Claire
C
Simons
Paul J
PJ
Nicholls
H John
HJ
Smith
D000818:Animals; D002072:Butylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015394:Molecular Structure; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000378:metabolism*
D002072:Butylene Glycols; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D014212:Tretinoin