Inhibition of Cytochrome P450 Enzymes by the E- and Z-Isomers of Norendoxifen

Abstract

Aromatase catalyzes the conversion of testosterone to estradiol and is the main source of endogenous estrogen in postmenopausal women. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone receptor-positive breast cancer. Norendoxifen [4-(1-(4-(2-aminoethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol], an active metabolite of the selective estrogen receptor modulator tamoxifen, has been shown to be a potent competitive AI, with an IC 50 of 90 nM. To obtain data relevant to the clinical use of norendoxifen, the primary objective of this study was to investigate norendoxifen's inhibitory capability on enzymes related to drug-drug interactions. We determined the inhibitory ability of norendoxifen against important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E-and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with K i values of 70 6 9, 76 6 3, 375 6 6, 829 6 62, and 0.56 6 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E-and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.

Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen‐treated Asian breast cancer patients

“…In addition, Liu et al . also demonstrated the high selectivity of NorEND toward aromatase (CYP19) among other CYP450 enzymes, including CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A , therefore suggesting that NorEND is a potent and selective aromatase inhibitor. NorEND has been previously shown to antagonize the activity of estrogen receptors in breast tissues, although its antagonism is reportedly weaker than those observed with (Z)‐4‐OHT and endoxifen .…”

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

“…These results are generally consistent with those previously reported for structurally related compounds. 19, 20, 31, 32 …”

Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors

“…The bisphenol 9 was first prepared by McMurry cross-coupling of acetophenone ( 8 ) with 4,4'-dihydroxybenzophenone as described. 25 The bisphenol 9 was treated with an excess of MOMCl to afford the di-protected product 10 in good yield. The protected intermediate 10 underwent a series of reactions, including bromination with NBS, alkylation of potassium cyanide, and deprotection of the MOM groups with HCl to afford the nitrile 11 in very good yield.…”

“…24 Biological testing results confirmed the aromatase inhibitory activity of ( E,Z )-norendoxifen and further established high affinity for both ER-α and ER-β (Figure 2), establishing ( E,Z )-norendoxifen the first substance with potential dual AI and ER binding activity. 24, 25 The E - and Z -norendoxifen isomers ( E -5 and Z -5 ) were also prepared via stereoselective synthetic routes, and their biological activities revealed that E -norendoxifen is the more potent aromatase inhibitor, while Z -norendoxifen displayed greater affinity for both ER-α and ER-β. 24 To optimize efficacy and CYP selectivity, a series of norendoxifen analogues were subsequently designed and prepared using a structure-based drug design approach.…”