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Joseph T Lundquist,
Douglas C Harnish,
Callain Y Kim,
John F Mehlmann,
Rayomand J Unwalla,
Kristin M Phipps,
Matthew L Crawley,
Thomas Commons,
Daniel M Green,
Weixin Xu,
Wah-Tung Hum,
Julius E Eta,
Irene Feingold,
Vikram Patel,
Mark J Evans,
Kehdih Lai, Lisa Borges-Marcucci,
Paige E Mahaney,
Jay E Wrobel
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ABSTRACT: In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
Journal of Medicinal Chemistry 02/2010; 53(4):1774-87. · 4.80 Impact Factor
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Mark J Evans,
Paige E Mahaney, Lisa Borges-Marcucci,
KehDih Lai,
Shuguang Wang,
Julie A Krueger,
Stephen J Gardell,
Christine Huard,
Robert Martinez,
George P Vlasuk,
Douglas C Harnish
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ABSTRACT: The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor-/- mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-alpha agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR-/- mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.
AJP Gastrointestinal and Liver Physiology 02/2009; 296(3):G543-52. · 3.43 Impact Factor
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Thomas J Caggiano,
Antony Brazzale,
Douglas M Ho,
Christina M Kraml,
Eugene Trybulski,
Christopher C Chadwick,
Sue Chippari, Lisa Borges-Marcucci,
Amy Eckert,
James C Keith,
Thomas Kenney,
Douglas C Harnish
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ABSTRACT: Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.
Journal of Medicinal Chemistry 12/2007; 50(22):5245-8. · 5.25 Impact Factor
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Robert J Steffan,
Edward Matelan,
Mark A Ashwell,
William J Moore,
William R Solvibile,
Eugene Trybulski,
Christopher C Chadwick,
Susan Chippari,
Thomas Kenney,
Richard C Winneker,
Amy Eckert, Lisa Borges-Marcucci,
Steven J Adelman,
Zhang Xu,
Lydia Mosyak,
Douglas C Harnish
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ABSTRACT: The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Current Topics in Medicinal Chemistry 02/2006; 6(2):103-11. · 4.17 Impact Factor
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Christopher C Chadwick,
Susan Chippari,
Edward Matelan, Lisa Borges-Marcucci,
Amy M Eckert,
James C Keith,
Leo M Albert,
Yelena Leathurby,
Heather A Harris,
Ramesh A Bhat,
Mark Ashwell,
Eugene Trybulski,
Richard C Winneker,
Steven J Adelman,
Robert J Steffan,
Douglas C Harnish
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ABSTRACT: Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.
Proceedings of the National Academy of Sciences 03/2005; 102(7):2543-8. · 9.68 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial proliferation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-kappaB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 transgenic rat and the Lewis rat adjuvant-induced model, after daily oral administration. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, alpha1-acid glycoprotein (alpha1-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstrate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-alpha-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-kappaB transcriptional activity.
Arthritis research & therapy 02/2005; 7(3):R427-38. · 4.27 Impact Factor
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Robert J Steffan,
Edward Matelan,
Mark A Ashwell,
William J Moore,
William R Solvibile,
Eugene Trybulski,
Christopher C Chadwick,
Susan Chippari,
Thomas Kenney,
Amy Eckert, Lisa Borges-Marcucci,
James C Keith,
Zhang Xu,
Lydia Mosyak,
Douglas C Harnish
[show abstract]
[hide abstract]
ABSTRACT: Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
Journal of Medicinal Chemistry 01/2005; 47(26):6435-8. · 5.25 Impact Factor
