Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

Bingwei V. Yang; David S. Weinstein; Lidia M. Doweyko; Hua Gong; Wayne Vaccaro; Tram Huynh; Hai Yun Xiao; Arthur M. Doweyko; Lorraine McKay; Deborah A. Holloway; John E. Somerville; Sium Habte; Mark Cunningham; Michele McMahon; Robert Townsend; David Shuster; John H. Dodd; Steven G. Nadler; Joel C. Barrish

doi:10.1021/jm100957a

Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

Bingwei V. Yang, David S. Weinstein, Lidia M. Doweyko, Hua Gong, Wayne Vaccaro, Tram Huynh, Hai Yun Xiao, Arthur M. Doweyko, Lorraine McKay, Deborah A. Holloway, John E. Somerville, Sium Habte, Mark Cunningham, Michele McMahon, Robert Townsend, David Shuster, John H. Dodd, Steven G. Nadler, Joel C. Barrish

Chemistry

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.

Original language	English (US)
Pages (from-to)	8241-8251
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	23
DOIs	https://doi.org/10.1021/jm100957a
State	Published - Dec 9 2010

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/jm100957a

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Yang, B. V., Weinstein, D. S., Doweyko, L. M., Gong, H., Vaccaro, W., Huynh, T., Xiao, H. Y., Doweyko, A. M., McKay, L., Holloway, D. A., Somerville, J. E., Habte, S., Cunningham, M., McMahon, M., Townsend, R., Shuster, D., Dodd, J. H., Nadler, S. G., & Barrish, J. C. (2010). Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists. Journal of Medicinal Chemistry, 53(23), 8241-8251. https://doi.org/10.1021/jm100957a

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title = "Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists",

abstract = "A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.",

author = "Yang, {Bingwei V.} and Weinstein, {David S.} and Doweyko, {Lidia M.} and Hua Gong and Wayne Vaccaro and Tram Huynh and Xiao, {Hai Yun} and Doweyko, {Arthur M.} and Lorraine McKay and Holloway, {Deborah A.} and Somerville, {John E.} and Sium Habte and Mark Cunningham and Michele McMahon and Robert Townsend and David Shuster and Dodd, {John H.} and Nadler, {Steven G.} and Barrish, {Joel C.}",

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doi = "10.1021/jm100957a",

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Yang, BV, Weinstein, DS, Doweyko, LM, Gong, H, Vaccaro, W, Huynh, T, Xiao, HY, Doweyko, AM, McKay, L, Holloway, DA, Somerville, JE, Habte, S, Cunningham, M, McMahon, M, Townsend, R, Shuster, D, Dodd, JH, Nadler, SG & Barrish, JC 2010, 'Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists', Journal of Medicinal Chemistry, vol. 53, no. 23, pp. 8241-8251. https://doi.org/10.1021/jm100957a

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T1 - Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

AU - Yang, Bingwei V.

AU - Weinstein, David S.

AU - Doweyko, Lidia M.

AU - Gong, Hua

AU - Vaccaro, Wayne

AU - Huynh, Tram

AU - Xiao, Hai Yun

AU - Doweyko, Arthur M.

AU - McKay, Lorraine

AU - Holloway, Deborah A.

AU - Somerville, John E.

AU - Habte, Sium

AU - Cunningham, Mark

AU - McMahon, Michele

AU - Townsend, Robert

AU - Shuster, David

AU - Dodd, John H.

AU - Nadler, Steven G.

AU - Barrish, Joel C.

PY - 2010/12/9

Y1 - 2010/12/9

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AB - A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.

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Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

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