Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity

被引：31

作者：

Smith, CJ

Ali, A

Balkovec, JM

Graham, DW

Hammond, ML

Patel, GF

Rouen, GP

Smith, SK

Tata, JR

Einstein, M

Ge, L

Harris, GS

Kelly, TM

Mazur, P

Thompson, CM

Wang, CLF

Williamson, JM

Miller, DK

Pandit, S

Santoro, JC

Sitlani, A

Yamin, TD

O'Neill, EA

Zaller, DM

Carballo-Jane, E

Forrest, MJ

Luell, S

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Cardiovasc Dis, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Immunol, Rahway, NJ 07065 USA

[5] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 11期

关键词：

glucocorticoid; dissociation; transrepression; transactivation; inflammation;

D O I：

10.1016/j.bmcl.2005.03.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED50 Of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：2926 / 2931

页数：6

共 36 条

[1] Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor:: Receptor binding and in vivo activity [J].

Ali, A ;

Thompson, CF ;

Balkovec, JM ;

Graham, DW ;

Hammond, ML ;

Quraishi, N ;

Tata, JR ;

Einstein, M ;

Ge, L ;

Harris, G ;

Kelly, TM ;

Mazur, P ;

Pandit, S ;

Santoro, J ;

Sitlani, A ;

Wang, CL ;

Williamson, J ;

Miller, DK ;

Thompson, CM ;

Zaller, DM ;

Forrest, MJ ;

Carballo-Jane, E ;

Luell, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) :2441-2452

[2]

[Anonymous], 1985, ORG SYNTH

[3]

Buchschacher P., 1990, ORG SYNTH, VVII, P368

[4] An efficient, rapid and highly selective preparation of the Wieland-Miescher ketone-9-ethylene ketal [J].

Ciceri, P ;

Demnitz, FWJ .

TETRAHEDRON LETTERS, 1997, 38 (03) :389-390

[5] A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects [J].

Coghlan, MJ ;

Jacobson, PB ;

Lane, B ;

Nakane, M ;

Lin, CW ;

Elmore, SW ;

Kym, PR ;

Luly, JR ;

Carter, GW ;

Turner, R ;

Tyree, CM ;

Hu, JL ;

Elgort, M ;

Rosen, J ;

Miner, JN .

MOLECULAR ENDOCRINOLOGY, 2003, 17 (05) :860-869

[6] The pursuit of differentiated ligands for the glucocorticoid receptor [J].

Coghlan, MJ ;

Elmore, SW ;

Kym, PR ;

Kort, ME .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2003, 3 (14) :1617-1635

[7] Selective glucocorticold receptor modulators [J].

Coghlan, MJ ;

Elmore, SW ;

Kym, PR ;

Kort, ME .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 37, 2002, 37 :167-176

[8] Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective quinoline derivatives with prednisolone-equivalent functional activity [J].

Coghlan, MJ ;

Kym, PR ;

Elmore, SW ;

Wang, AX ;

Luly, JR ;

Wilcox, D ;

Stashko, M ;

Lin, CW ;

Miner, J ;

Tyree, C ;

Nakane, M ;

Jacobson, P ;

Lane, BC .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :2879-2885

[9] Novel ligands of steroid hormone receptors [J].

Coghlan, MJ ;

Kort, ME .

EXPERT OPINION ON THERAPEUTIC PATENTS, 1999, 9 (11) :1523-1536

[10] Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators [J].

Elmore, SW ;

Pratt, JK ;

Coghlan, MJ ;

Mao, Y ;

Green, BE ;

Anderson, DD ;

Stashko, MA ;

Lin, CW ;

Falls, D ;

Nakane, M ;

Miller, L ;

Tyree, CM ;

Miner, JN ;

Lane, B .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (07) :1721-1727

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