Dissociated nonsteroidal glucocorticoid receptor modulators; Discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series

被引：79

作者：

Barker, Mike ^{[1
]}

Clackers, Margaret ^{[1
]}

Copley, Royston ^{[1
]}

Demaine, Derek A. ^{[1
]}

Humphreys, Davina ^{[1
]}

Inglis, Graham G. A. ^{[1
]}

Johnston, Michael J. ^{[1
]}

Jones, Haydn T. ^{[1
]}

Haase, Michael V. ^{[1
]}

House, David ^{[1
]}

Loiseau, Richard ^{[1
]}

Nisbet, Lesley ^{[1
]}

Pacquet, Francois ^{[1
]}

Skone, Philip A. ^{[1
]}

Shanahan, Stephen E. ^{[1
]}

Tape, Dan ^{[1
]}

Vinader, Victoria M. ^{[1
]}

Washington, Melanie ^{[1
]}

Uings, Iain ^{[1
]}

Upton, Richard ^{[1
]}

Mclay, Iain M. ^{[1
]}

Macdonald, Simon J. F. ^{[1
]}

机构：

[1] RI CEDD, GlaxoSmithKline Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 14期

关键词：

D O I：

10.1021/jm060302x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

引用

页码：4216 / 4231

页数：16

共 41 条

[31]

MORGAN BP, 2004, LETT DRUG DES DISCOV, V1, P1

[32] SYNTHESIS AND EVALUATION OF N,N-DI-N-PROPYLTETRAHYDROBENZ[F]INDOL-7-AMINE AND RELATED CONGENERS AS DOPAMINERGIC AGONISTS [J].

NICHOLS, DE ;

CASSADY, JM ;

PERSONS, PE ;

YEUNG, MC ;

CLEMENS, JA ;

SMALSTIG, EB .

JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (09) :2128-2134

[33] Therapeutic potential of selective modulators of nuclear receptor action [J].

Resche-Rigon, M ;

Gronemeyer, H .

CURRENT OPINION IN CHEMICAL BIOLOGY, 1998, 2 (04) :501-507

[34] Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects [J].

Schäcke, H ;

Schottelius, A ;

Döcke, WD ;

Strehlke, P ;

Jaroch, S ;

Schmees, N ;

Rehwinkel, H ;

Hennekes, H ;

Asadullah, K .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (01) :227-232

[35] Mechanisms involved in the side effects of glucocorticoids [J].

Schäcke, H ;

Döcke, WD ;

Asadullah, K .

PHARMACOLOGY & THERAPEUTICS, 2002, 96 (01) :23-43

[36]

Schimmer B.P., 2001, GOODMAN GILLMANS PHA, P1649

[37] Design and evaluation of novel nonsteroidal dissociating glucocorticoid receptor ligands [J].

Shah, N ;

Scanlan, TS .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (20) :5199-5203

[38] Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity [J].

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 .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (11) :2926-2931

[39] Novel heterocyclic glucocorticoids: in vitro profile and in vivo efficacy [J].

Thompson, CF ;

Quraishi, N ;

Ali, A ;

Tata, JR ;

Hammond, ML ;

Balkovec, JM ;

Einstein, M ;

Ge, L ;

Harris, G ;

Kelly, TM ;

Mazur, P ;

Pandit, S ;

Santoro, J ;

Sitlani, A ;

Wang, CL ;

Williamson, J ;

Miller, DK ;

Yamin, TTD ;

Thompson, CM ;

O'Neill, EA ;

Zaller, D ;

Forrest, MJ ;

Carballo-Jane, E ;

Luell, S .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (08) :2163-2167

[40] Chemical activation of innate and specific immunity in contact dermatitis [J].

Zhang, L ;

Tinkle, SS .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2000, 115 (02) :168-176

← 1 2 3 4 5 →