Novel retinoic acid 4-hydroxylase (CYP26) inhibitors based on a 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl scaffold.
Retinoic acid (RA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases including dermatological conditions and cancer. The antiproliferative effects of RA have been well documented as well as the limitations owing to toxicity and the development of resistance to RA therapy. RA metabolism inhibitors (RAMBAs or CYP26 inhibitors) are attracting increasing interest as an alternative method for enhancing endogenous levels of retinoic acid in the treatment of hyperproliferative disease. Here the synthesis and inhibitory activity of novel 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl derivatives in a MCF-7 CYP26A1 microsomal assay are described. The most promising inhibitor methyl 2,2-dimethyl-3-(4-(phenylamino)phenyl)-3-(1H-1,2,4-triazol-1-yl)propanoate (6) exhibited an IC(50) of 13 nM (compared with standards Liarozole IC(50) 540 nM and R116010 IC(50) 10 nM) and was further evaluated for CYP selectivity using a panel of CYP with >100-fold selectivity for CYP26 compared with CYP1A2, 2C9 and 2D6 observed and 15-fold selectivity compared with CYP3A4. The results demonstrate the potential for further development of these potent inhibitors.
Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Mohamed S
MS
Gomaa
Caroline E
CE
Bridgens
Nicola A
NA
Illingworth
Gareth J
GJ
Veal
Christopher P F
CP
Redfern
Andrea
A
Brancale
Jane L
JL
Armstrong
Claire
C
Simons
D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004952:Esters; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry*; D000072516:Retinoic Acid 4-Hydroxylase; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004952:Esters; D007093:Imidazoles; D011422:Propionates; D014230:Triazoles; C575839:methyl 2,2-dimethyl-3-(4-(phenylamino)phenyl)-3-(1H-1,2,4-triazol-1-yl)propanoate; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase