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11 results on '"Rhönnstad P"'

3. Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist

Author

Schnute, Mark E., Wennerstål, Mattias, Alley, Jennifer, Bengtsson, Martin, Blinn, James R., Bolten, Charles W., Braden, Timothy, Bonn, Tomas, Carlsson, Bo, Caspers, Nicole, Chen, Ming, Choi, Chulho, Collis, Leon P., Crouse, Kimberly, Färnegårdh, Mathias, Fennell, Kimberly F., Fish, Susan, Flick, Andrew C., Goos-Nilsson, Annika, Gullberg, Hjalmar, Harris, Peter K., Heasley, Steven E., Hegen, Martin, Hromockyj, Alexander E., Hu, Xiao, Husman, Bolette, Janosik, Tomasz, Jones, Peter, Kaila, Neelu, Kallin, Elisabet, Kauppi, Björn, Kiefer, James R., Knafels, John, Koehler, Konrad, Kruger, Lars, Kurumbail, Ravi G., Kyne, Robert E., Li, Wei, Löfstedt, Joakim, Long, Scott A., Menard, Carol A., Mente, Scot, Messing, Dean, Meyers, Marvin J., Napierata, Lee, Nöteberg, Daniel, Nuhant, Philippe, Pelc, Matthew J., Prinsen, Michael J., Rhönnstad, Patrik, Backström-Rydin, Eva, Sandberg, Johnny, Sandström, Maria, Shah, Falgun, Sjöberg, Maria, Sundell, Aron, Taylor, Alexandria P., Thorarensen, Atli, Trujillo, John I., Trzupek, John D., Unwalla, Ray, Vajdos, Felix F., Weinberg, Robin A., Wood, David C., Xing, Li, Zamaratski, Edouard, Zapf, Christoph W., Zhao, Yajuan, Wilhelmsson, Anna, and Berstein, Gabriel

Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Published
2018
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4. P.1.4: AN ESTROGEN RECEPTOR-β SELECTIVE AGONIST EXERTS SPECIFIC PRO-APOPTOTIC EFFECTS AND PROMOTES TUMOR REGRESSION IN A RAT MODEL OF INTRA-HEPATIC CHOLANGIOCARCINOMA

Author

Marzioni, M., primary, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Pierantonelli, I., additional, Rhönnstad, P., additional, Trozzi, L., additional, Saccomanno, S., additional, Apelqvist, T., additional, Gentile, R., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, De Minicis, S., additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2011
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5. 238 AN ESTROGEN RECEPTOR ß SELECTIVE AGONIST EXERTS SPECIFIC PRO-APOPTOTIC EFFECTS AND PROMOTES TUMOR REGRESSION IN A RAT MODEL OF INTRA-HEPATIC CHOLANGIOCARCINOMA

Author

Marzioni, M., primary, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Pierantonelli, I., additional, Rhönnstad, P., additional, Trozzi, L., additional, Saccomanno, S., additional, Apelqvist, T., additional, Gentile, R., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, De Minicis, S., additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2011
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6. OC2 An estrogen receptor β selective agonist exerts specific pro-apoptotic effects and promotes tumor regression in a rat model of intra-hepatic cholangiocarcinoma

Author

Marzioni, M., primary, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Pierantonelli, I., additional, Rhönnstad, P., additional, Trozzi, L., additional, Saccomanno, S., additional, Apelqvist, T., additional, Gentile, R., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, Minicis, S. De, additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2010
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7. 880 ESTROGEN RECEPTOR β SELECTIVE AGONISTS EXERT ANTI-CANCER ACTIVITY ON EXPERIMENTAL INTRA-HEPATIC CHOLANGIOCARCINOMA: AN IN VITRO AND IN VIVO STUDY

Author

Marzioni, M., primary, Saccomanno, S., additional, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Rhönnstad, P., additional, Trozzi, L., additional, Apelqvist, T., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2010
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8. OC.05.2 ESTROGEN RECEPTOR β SELECTIVE AGONISTS EXERT ANTI-CANCER ACTIVITY ON EXPERIMENTAL INTRA-HEPATIC CHOLANGIOCARCINOMA: AN IN VITRO AND IN VIVO STUDY

Author

Marzioni, M., primary, Saccomanno, S., additional, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Rhönnstad, P., additional, Trozzi, L., additional, Apelqvist, T., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2010
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9. 14 ESTROGEN RECEPTOR β SELECTIVE AGONISTS EXERT ANTI-CANCER ACTIVITY ON EXPERIMENTAL INTRA-HEPATIC CHOLANGIOCARCINOMA: AN IN VITRO AND IN VIVO STUDY

Author

Marzioni, M., primary, Saccomanno, S., additional, Torrice, A., additional, Rychlicki, C., additional, Agostinelli, L., additional, Rhönnstad, P., additional, Trozzi, L., additional, Apelqvist, T., additional, Candelaresi, C., additional, Fava, G., additional, Benedetti, A., additional, Gaudio, E., additional, Kallin, E., additional, Alvaro, D., additional, and Nilsson, S., additional

Published
2010
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10. An oestrogen receptor β-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma.

Author

Marzioni, Marco, Torrice, Alessia, Saccomanno, Stefania, Rychlicki, Chiara, Agostinelli, Laura, Pierantonelli, Irene, Rhönnstad, Patrik, Trozzi, Luciano, Apelqvist, Theresa, Gentile, Raffaele, Candelaresi, Cinzia, Fava, Giammarco, Semeraro, Rossella, Benedetti, Antonio, Gaudio, Eugenio, Franchitto, Antonio, Onori, Paolo, De Minicis, Samuele, Carpino, Guido, and Kallin, Elisabet

Subjects
ESTROGEN receptors, ANTINEOPLASTIC agents, CHOLANGIOCARCINOMA, APOPTOSIS, CANCER cell proliferation, DRUG development, SMALL interfering RNA
Abstract

Abstract: Background: Cholangiocarcinoma cells over-express oestrogen receptor-β, which displays anti-proliferative and pro-apoptotic effects. Aim: To evaluate the effects of a newly developed and highly selective oestrogen receptor-β agonist (KB9520) on experimental intrahepatic cholangiocarcinoma. Methods: In vitro, the effects of KB9520 on apoptosis and proliferation of HuH-28 cells, HuH-28 cells with selective oestrogen receptor-β silencing (by small interfering RNA), HepG2 cells (oestrogen receptor-α and oestrogen receptor-β negative) and HepER3 cells (HepG2 cells transformed to stably express oestrogen receptor-α) were evaluated. In vivo, the effects of KB9520 on experimental intrahepatic cholangiocarcinoma, induced by thioacetamide administration were tested. Results: In vitro, KB9520 induced apoptosis and inhibited proliferation of HuH-28 cells. KB9520 effects were absent in cells lacking oestrogen receptor-α and β (HepG2) and in cells expressing only oestrogen receptor-α (HepER3); its pro-apoptotic effect was impaired in cells where oestrogen receptor-β expression was decreased by specific small interfering RNA. In vivo, KB9520 inhibited experimental intrahepatic cholangiocarcinoma development in thioacetamide-treated rats and promoted tumour regression in rats where tumour was already established. In treated animals, tumour areas showed reduced proliferation but increased apoptosis. Conclusions: KB9520 induced apoptosis in cholangiocarcinoma by selectively acting on oestrogen receptor-β, suggesting that oestrogen receptor-β selective agonists may be a novel and effective therapeutic option for the medical treatment of intrahepatic cholangiocarcinoma. [Copyright &y& Elsevier]

Published
2012
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11. Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.

Author

Schnute ME, Wennerstål M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers N, Chen M, Choi C, Collis LP, Crouse K, Färnegårdh M, Fennell KF, Fish S, Flick AC, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels J, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Löfstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Nöteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhönnstad P, Backström-Rydin E, Sandberg J, Sandström M, Shah F, Sjöberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, and Berstein G

Subjects
Administration, Oral, Animals, Biological Availability, Drug Evaluation, Preclinical, Humans, Mice, Pyridines pharmacokinetics, Th17 Cells drug effects, Th17 Cells metabolism, Drug Design, Drug Inverse Agonism, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Pyridines administration & dosage, Pyridines pharmacology
Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Published
2018
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