Discovery of small molecule antagonists of TRPV1

被引：53

作者：

Rami, HK

Thompson, M

Wyman, P

Jerman, JC

Egerton, J

Brough, S

Stevens, AJ

Randall, AD

Smart, D

Gunthorpe, MJ

Davis, JB

机构：

[1] GlaxoSmithKline, Neurol & GI CEDD, Harlow CM19 5AW, Essex, England

[2] GlaxoSmithKline, Psychiat CEDD, Harlow CM19 5AW, Essex, England

[3] GlaxoSmithKline, Discovery Res, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 14期

关键词：

TRPV1; vanilloid antagonist; VR1; SB-452533; SB-366791;

D O I：

10.1016/j.bmcl.2004.05.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca2+ based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPVI. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPVI receptor. (C) 2004 Elsevier Ltd. All rights reserved.

引用

收藏

页码：3631 / 3634

页数：4

相关论文

共 20 条

[1]

BAKTHAVATCHALAM R, 2002, Patent No. 0208221

[2] Vanilloid and TRP channels: a family of lipid-gated cation channels [J].

Benham, CD ;

Davis, JB ;

Randall, AD .

NEUROPHARMACOLOGY, 2002, 42 (07) :873-888

[3] CAPSAZEPINE - A COMPETITIVE ANTAGONIST OF THE SENSORY NEURON EXCITANT CAPSAICIN [J].

BEVAN, S ;

HOTHI, S ;

HUGHES, G ;

JAMES, IF ;

RANG, HP ;

SHAH, K ;

WALPOLE, CSJ ;

YEATS, JC .

BRITISH JOURNAL OF PHARMACOLOGY, 1992, 107 (02) :544-552

[4]

BO Y, 2003, Patent No. 03049702

[5] The capsaicin receptor: a heat-activated ion channel in the pain pathway [J].

Caterina, MJ ;

Schumacher, MA ;

Tominaga, M ;

Rosen, TA ;

Levine, JD ;

Julius, D .

NATURE, 1997, 389 (6653) :816-824

[6] Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture [J].

Docherty, RJ ;

Yeats, JC ;

Piper, AS .

BRITISH JOURNAL OF PHARMACOLOGY, 1997, 121 (07) :1461-1467

[7] Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery [J].

Forrest, JB ;

Camu, F ;

Greer, IA ;

Kehlet, H ;

Abdalla, M ;

Bonnet, F ;

Ebrahim, S ;

Escolar, G ;

Jage, J ;

Pocock, S ;

Velo, G ;

Langman, MJS ;

Porro, GB ;

Samama, MM ;

Heitlinger, E .

BRITISH JOURNAL OF ANAESTHESIA, 2002, 88 (02) :227-233

[8] Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist [J].

Gunthorpe, MJ ;

Rami, HK ;

Jerman, JC ;

Smart, D ;

Gill, CH ;

Soffin, EM ;

Hannan, SL ;

Lappin, SC ;

Egerton, J ;

Smith, GD ;

Worby, A ;

Howett, L ;

Owen, D ;

Nasir, S ;

Davies, CH ;

Thompson, M ;

Wyman, PA ;

Randall, AD ;

Davis, JB .

NEUROPHARMACOLOGY, 2004, 46 (01) :133-149

[9] The diversity in the vanilloid (TRPV) receptor family of ion channels [J].

Gunthorpe, MJ ;

Benham, CD ;

Randall, A ;

Davis, JB .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2002, 23 (04) :183-191

[10] Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors [J].

Jerman, JC ;

Gray, J ;

Brough, SJ ;

Ooi, L ;

Owen, D ;

Davis, JB ;

Smart, D .

BRITISH JOURNAL OF ANAESTHESIA, 2002, 89 (06) :882-887