title: The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
abstract: o-Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o-quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o-quinone (t(1/2)=3.9 ± 0.1h) which like 4-hydroxyequilenin-o-quinone (t(1/2)=2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o-quinones, which were characterized by LC-MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o-quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N-dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen quinones and o-quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o-quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o-quinones, the formation of these quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, M/C 781, Chicago, IL 60612-7231, USA.
authors.forename: Teshome B
authors.initials: TB
authors.lastname: Gherezghiher
authors.forename: Bradley
authors.initials: B
authors.lastname: Michalsen
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Qin
authors.forename: Johann
authors.initials: J
authors.lastname: Sohn
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004855:Equilenin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: C504960:LY2066948; D009281:Naphthalenes; D010880:Piperidines; D011809:Quinones; D020845:Selective Estrogen Receptor Modulators; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004855:Equilenin