New non-steroidal aromatase inhibitors: Focus on R76713

Coster, R. De; Wouters, Walter; Bowden, Charles R.; Bossche, H. Vanden; Bruynseels, J.; Tuman, Robert W.; Ginckel, R. Van; Snoeck, Eric; Peer, Achiel Van; Janßen, Paul

doi:10.1016/0960-0760(90)90482-z

Cited by 54 publications

(19 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4, b and c). Although the (ϩ) enantiomer of vorozole is substantially more potent than the (Ϫ) enantiomer in aromatase inhibition (De Coster et al, 1990;Goss, 1998), the results reported here show that the (Ϫ) enantiomer may be more potent with respect to P450 induction.…”

Section: Discussionmentioning

confidence: 62%

“…The compounds studied included several reported to induce CYP1A alone or together with CYP2 enzymes in mammalian liver or cultured cells: albendazole, benzylimidazole, omeprazole, and thiabendazole (Papac and Franklin, 1988;Souhaili-el Amri et al, 1988;Aix et al, 1994;Curi-Pedrosa et al, 1994;Rey-Grobellet et al, 1996;Price et al, 2004). In addition, we examined the effect of a third-generation aromatase inhibitor, the triazole derivative vorozole (De Coster et al, 1990;Goss, 1998) for which reports of P450-inducing activities were not found.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Induction of Cyp1a and Cyp2-Mediated Arachidonic Acid Epoxygenation and Suppression of 20-Hydroxyeicosatetraenoic Acid by Imidazole Derivatives Including the Aromatase Inhibitor Vorozole

Diani-Moore¹,

Papachristou²,

Labitzke³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Cytochrome P450 (P450) enzymes metabolize the membrane lipid arachidonic acid to stable biologically active epoxides [eicosatrienoic acids (EETs)] and 20-hydroxyeicosatetraenoic acid (20-HETE). These products have cardiovascular activity, primarily acting as vasodilators and vasoconstrictors, respectively. EET formation can be increased by the prototype CYP1A or CYP2 inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or phenobarbital (PB), respectively. We report here that imidazole derivative drugs: the anthelminthics, albendazole and thiabendazole; the proton pump inhibitor, omeprazole; the thromboxane synthase inhibitor, benzylimidazole; and the aromatase (CYP19) inhibitor vorozole (R76713, racemate; and R83842, (؉) enantiomer) increased hepatic microsomal EET formation in a chick embryo model. Albendazole increased EETs by transcriptional induction of CYP1A5 and the others by combined induction of CYP1A5 and CYP2H, the avian orthologs of mammalian CYP1A2 and CYP2B, respectively. All inducers increased formation of the four EET regioisomers, but TCDD and albendazole had preference for 5,6-EET and PB and omeprazole for 14,15-EET. Vorozole, benzylimidazole, and TCDD also suppressed 20-HETE formation. Vorozole was a remarkably effective and potent inducer of multiple hepatic P450s at a dose range which overlapped its inhibition of ovarian aromatase. Increased CYP1A activity in mouse Hepa 1-6 and human HepG2 cells by vorozole and other imidazole derivatives demonstrated applicability of the findings to mammalian cells. The findings suggest that changes in P450-dependent arachidonic acid metabolism may be a new source of side effects for drugs that induce CYP1A or CYP2. They demonstrate further that in vivo induction of multiple hepatic P450s produces additive increases in arachidonic acid epoxygenase activity and can occur concurrently with inhibition of ovarian aromatase activity.

show abstract

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Induction of Cyp1a and Cyp2-Mediated Arachidonic Acid Epoxygenation and Suppression of 20-Hydroxyeicosatetraenoic Acid by Imidazole Derivatives Including the Aromatase Inhibitor Vorozole

Diani-Moore¹,

Papachristou²,

Labitzke³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…These compounds included the following: the nonsteroidal aromatase inhibitor Vorozole [VOR; Coster et al, 1990), generously provided by Dr. R. DeCoster (Janssen Research Foundation, Beerse, Belgium); the steroidal aromatase inhibitor 1,4,6-androstatrien-3,17-dione (ATD; Steraloids, Wilton, NH) and one of its metabolites, 1,4,6-androstatrien-17␤-ol-3-one (17-OH-ATD; Steraloids) (Ellinwood et al, 1984); estradiol benzoate (EB) and 17␤-estradiol (E 2 ; SigmaAldrich, Bornem, Belgium).…”

Section: Subjects and General Proceduresmentioning

confidence: 99%

Sexual Behavior Activity Tracks Rapid Changes in Brain Estrogen Concentrations

Taziaux

Keller

Bakker

et al. 2007

Journal of Neuroscience

View full text Add to dashboard Cite

Estrogens are classically viewed as hormones that bind to intracellular receptors, which then act as transcription factors to modulate gene expression; however, they also affect many aspects of neuronal functioning by rapid nongenomic actions. Brain estrogen production can be regulated within minutes by changes in aromatase (estrogen synthase) activity as a result of calcium-dependent phosphorylations of the enzyme. To determine the effects of rapid changes in estrogen availability on male copulatory behavior, we mimicked in male mice the rapid upregulation and downregulation of brain estrogen concentration that should occur after inactivation or activation of aromatase activity. A single injection of different aromatase inhibitors [Vorozole, 1,4,6-androstatrien-3,17-dione (ATD), or its metabolite 17-OH-ATD (1,4,6-androstatrien-17␤-ol-3-one)] almost completely suppressed male sexual behavior (mounts and intromissions) expressed 10 -20 min later by C57BL/6J mice but did not affect behavior in aromatase knock-out (ArKO) mice, activated by daily injections of estradiol benzoate, thereby confirming the specificity of the behavioral inhibition observed in wild-type mice. The rapid ATD-induced inhibition was reversed by the simultaneous injection of a large dose of estradiol. A single injection of estradiol to ArKO mice also activated male sexual behavior within 15 min. Thus, rapid increases or decreases in brain estrogen concentrations are followed within minutes by corresponding changes in male sexual behavior. Sexual behavior can thus be used to monitor changes in local estrogen concentrations and analyze the mechanisms mediating the rapid decline in estrogen signaling that takes place after inhibition of estrogen synthesis.

show abstract

“…In addition two furan derivatives (9) were also prepared to assess the role of the benzene component of the benzofuran ring in enzyme binding. …”

Section: Introductionmentioning

confidence: 99%

“…fadrazole (2) and vorozole (3), which are more specific inhibitors of the target enzyme [7] than the well established inhibitor aminoglutethimide (4, AG), and do not possess certain undesirable side effects of the latter [8]. Liarazole w (5), an azolyl-substituted benzimidazole [9], and the 1-[(benzofuran-2-yl)phenylmethyl]-imidazoles [10] (6) and triazoles [11] (7), are also potent P450 AROM inhibitors. These inhibitors bind to the active site of P450 AROM through coordination of a heterocyclic nitrogen lone pair of electrons with the Fe 3þ of the haem in the active site of the enzyme, therefore the coordination potential of the heterocyclic nitrogen is of importance.…”

Section: Introductionmentioning

confidence: 99%

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Saberi

Shah

Simons

2005

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives were prepared using an efficient 1-step procedure in good yields. In addition furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were also prepared to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P450 AROM , CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives showed good to moderate activity ðIC 50 ¼ 1:3 -25:1 mMÞ; which was either better than or comparable with aminoglutethimide ðIC 50 ¼ 18:5 mMÞ but lower than arimidex ðIC 50 ¼ 0:6 mMÞ; with the 4-methoxyphenyl substituted derivative displaying optimum activity. Molecular modelling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivative suggested activity to reside with the (S)-enantiomer. The furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity indicating the essential role of the benzene ring of the benzofuran component for enzyme binding.

show abstract

New non-steroidal aromatase inhibitors: Focus on R76713

Cited by 54 publications

References 20 publications

Induction of Cyp1a and Cyp2-Mediated Arachidonic Acid Epoxygenation and Suppression of 20-Hydroxyeicosatetraenoic Acid by Imidazole Derivatives Including the Aromatase Inhibitor Vorozole

Induction of Cyp1a and Cyp2-Mediated Arachidonic Acid Epoxygenation and Suppression of 20-Hydroxyeicosatetraenoic Acid by Imidazole Derivatives Including the Aromatase Inhibitor Vorozole

Sexual Behavior Activity Tracks Rapid Changes in Brain Estrogen Concentrations

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Contact Info

Product

Resources

About