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

36 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

@article{c59d314be04d4e239833d7d0c0b2ea7e,

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.\}",

year = "2010",

month = dec,

day = "9",

doi = "10.1021/jm100957a",

language = "English (US)",

volume = "53",

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journal = "Journal of Medicinal Chemistry",

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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

N2 - 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.

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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JO - Journal of Medicinal Chemistry

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IS - 23

ER -

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

Abstract

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