Synthesis and Activity of Substituted 4-(Indazol-3-yl)phenols as Pathway-Selective Estrogen Receptor Ligands Useful in the Treatment of Rheumatoid Arthritis

Steffan, Robert J.; Matelan, Edward; Ashwell, Mark A.; Moore, William; Solvibile, William R.; Trybulski, Eugene J.; Chadwick, Christopher C.; Chippari, Susan; Kenney, Thomas; Eckert, A.; Borges-Marcucci, Lisa; Keith, James C.; Zhang, Xu; Mosyak, Lydia; Harnish, Douglas C.

doi:10.1021/jm049194+

Cited by 69 publications

(36 citation statements)

References 9 publications

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“…Way-169916 was synthesized as described previously with minor modifications (Steffan et al, 2004). Comprehensive methods and synthesis scheme are detailed in the supplemental information.…”

Section: Methodsmentioning

confidence: 99%

Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

et al. 2009

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The concept of selective receptor modulators has been established for the nuclear steroid hormone receptors. Such selective modulators have been used therapeutically with great success in the treatment of cancer. However, this concept has not been examined with regard to the aryl hydrocarbon receptor (AHR) because of the latent toxicity commonly associated with AHR activation. AHR-mediated toxicity is primarily derived from AHR binding to its dioxin response element (DRE) and driving expression of CYP1 family members, which have the capacity to metabolize procarcinogens to genotoxic carcinogens. Recent evidence using a non-DRE binding AHR mutant has established the DRE-independent suppression of inflammatory markers by the AHR. We wished to determine whether such DRE-independent repression with wild-type AHR could be dissociated from canonical DRE-dependent transactivation in a ligand-dependent manner and, in doing so, prove the concept of a selective AHR modulator (SAhRM). Here, we identify the selective estrogen receptor (ER) modulator Way-169916 as a dually selective modulator, binding both ER and AHR. Inflammatory gene expression associated with the cytokine-inducible acute-phase response (e.g., SAA1 and CRP) are diminished by Way-169916 in an AHR-dependent manner. Furthermore, activation of AHR by Way-169916 fails to stimulate canonical DREdriven AHR-mediated CYP1A1 expression, thus eliminating the potential for AHR-mediated genotoxic stress. Such anti-inflammatory activity in the absence of DRE-mediated expression fulfills the major criteria of an SAhRM, which suggests that selective modulation of AHR is possible and renders the AHR a therapeutically viable drug target for the amelioration of inflammatory disease.

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“…Way-169916 was synthesized as described previously with minor modifications (Steffan et al, 2004). Comprehensive methods and synthesis scheme are detailed in the supplemental information.…”

Section: Methodsmentioning

confidence: 99%

Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

et al. 2009

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“…This concept has led to the development of a selective estrogen receptor ligand, 4-[1-allyl-7-(trifluoromethyl)-1H-indazol-3-yl]benzene-1,3-diol (WAY-169916), which exhibits potent anti-inflammatory activity and has been demonstrated to effectively treat adjuvant induced arthritis (Steffan et al, 2004). We have established that WAY-169916 is also a selective AHR modulator (SAhRM) that is capable of repressing acute-phase gene expression (e.g., SAA1, CRP, HP) without inducing significant DRE-mediated transcriptional activity (Murray et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Cytokine-Mediated Complement Factor Gene Expression through Selective Activation of the Ah Receptor with 3′,4′-Dimethoxy-α-naphthoflavone

et al. 2010

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We have characterized previously a class of aryl hydrocarbon receptor (AHR) ligand termed selective AHR modulators (SAhRMs). SAhRMs exhibit anti-inflammatory properties, including suppression of cytokine-mediated acute phase genes (e.g., Saa1), through dissociation of non-dioxin-response element (DRE) AHR activity from DRE-dependent xenobiotic gene expression. The partial AHR agonist ␣-naphthoflavone (␣NF) mediates the suppressive, non-DRE dependent effects on SAA1 expression and partial DRE-mediated CYP1A1 induction. These observations suggest that ␣NF may be structurally modified to a derivative exhibiting only SAhRM activity. A screen of ␣NF derivatives identifies 3Ј,4Ј-dimethoxy-␣NF (DiMNF) as a candidate SAhRM. Competitive ligand binding validates DiMNF as an AHR ligand, and DRE-dependent reporter assays with quantitative mRNA analysis of AHR target genes reveal minimal agonist activity associated with AHR binding. Consistent with loss of agonist activity, DiMNF fails to promote AHR binding to DRE probes as determined through electromobility shift assay. Importantly, mRNA analysis indicates that DiMNF retains the suppressive capacity of ␣NF regarding cytokine-mediated SAA1 expression in Huh7 cells. Interestingly, predictive docking modeling suggests that DiMNF adopts a unique orientation within the AHR ligand binding pocket relative to ␣NF and may facilitate the rational design of additional SAhRMs. Microarray studies with a non-DRE binding but otherwise functional AHR mutant identified complement factor C3 as a potential SAhRM target. We confirmed this observation in Huh7 cells using 10 M DiMNF, which significantly repressed C3 mRNA and protein. These data expand the classes of AHR ligands exerting DRE-independent anti-inflammatory SAhRM activity, suggesting SAhRMs may have application in the amelioration of inflammatory disorders.

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“…Finally, the importance of understanding the unique pharmacology of tamoxifen can be placed in perspective. In retrospect, tamoxifen could, in fact, be viewed as the lead compound that was essential to initiate the synthesis of a broad range of new SERMs for the treatment of diseases as diverse as osteoporosis (86)(87)(88)(89)(90)(91)(92) and rheumatoid arthritis (93,94) and the subsequent extrapolation of the SERM concept to all members of the nuclear receptor superfamily (76). The advances documented with targeting tamoxifen now offer the promise of designing drugs to treat diseases previously thought to be impossible.…”

Section: Resultsmentioning

confidence: 99%

Tamoxifen: Catalyst for the change to targeted therapy

Jordan

2008

European Journal of Cancer

180

131

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In the early 1970's, a failed postcoital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk premenopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen's ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective estrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side effect of endometrial cancer noted in postmenopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.A new dynasty gives dominion over the ruling dynasty through perseverance and not by sudden action (Ibn Khaldun 14 th Century Arab Historian) -and so it is with changes in the approach to cancer therapy. This article will focus specifically on a cluster of scientific papers (1-3) published in the European Journal of Cancer that presaged the dramatic changes that have occurred in the past 35 years in our approach to cancer therapy. To set the scene, it is first appropriate to describe the research and treatment philosophy for breast cancer before tamoxifen.In the 1960's, the use of combination cytotoxic chemotherapy for the treatment of breast cancer had moved to center stage in the wake of an abstract presented at the American Association for Cancer Research (4). The cytotoxic "cocktail" presented by Cooper, containing cyclophosphamide, methotrexate, 5 fluorouracil, vincristine and prednisone (CMFVP), produced a dramatic response rate of >80% in patients with advanced breast cancer. In the 1960's, there was every reason to believe that cancer would be curable if 1) the right drug Correspondence: V. Craig Jordan, OBE, PhD, DSc, Vice President and Research Director for Medical Sciences, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, Phone: (215) Fax: (215) ...

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Synthesis and Activity of Substituted 4-(Indazol-3-yl)phenols as Pathway-Selective Estrogen Receptor Ligands Useful in the Treatment of Rheumatoid Arthritis

Cited by 69 publications

References 9 publications

Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

Evidence for Ligand-Mediated Selective Modulation of Aryl Hydrocarbon Receptor Activity

Suppression of Cytokine-Mediated Complement Factor Gene Expression through Selective Activation of the Ah Receptor with 3′,4′-Dimethoxy-α-naphthoflavone

Tamoxifen: Catalyst for the change to targeted therapy

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