Identification of (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea (ABT-102) as a potent TRPV1 antagonist for pain management

被引：71

作者：

Gomtsyan, Arthur ^{[1
]}

Bayburt, Erol K. ^{[1
]}

Schmidt, Robert G. ^{[1
]}

Surowy, Carol S. ^{[1
]}

Honore, Prisca ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Hannick, Steven M. ^{[1
]}

McDonald, Heath A. ^{[1
]}

Wetter, Jill M. ^{[1
]}

Sullivan, James P. ^{[1
]}

Jarvis, Michael F. ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Lee, Chih-Hung ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Neurosci Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 03期

关键词：

D O I：

10.1021/jm701007g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole-N'-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of (R)-7 (ABT-102). Both the analgesic activity and drug-like properties of (R)-7 support its advancement into clinical pain trials.

引用

页码：392 / 395

页数：4

共 22 条

[1] Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies [J].

Bley, KR .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2004, 13 (11) :1445-1456

[2] CONFORMATIONALLY RESTRICTED CONGENERS OF DOPAMINE DERIVED FROM 2-AMINOINDAN [J].

CANNON, JG ;

PEREZ, JA ;

BHATNAGAR, RK ;

LONG, JP ;

SHARABI, FM .

JOURNAL OF MEDICINAL CHEMISTRY, 1982, 25 (12) :1442-1446

[3] The vanilloid receptor: A molecular gateway to the pain pathway [J].

Caterina, MJ ;

Julius, D .

ANNUAL REVIEW OF NEUROSCIENCE, 2001, 24 :487-517

[4] 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

[5] TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists [J].

Cui, M. ;

Honore, P. ;

Zhong, C. ;

Gauvin, D. ;

Mikusa, J. ;

Hernandez, G. ;

Chandran, P. ;

Gomtsyan, A. ;

Brown, B. ;

Bayburt, E. K. ;

Marsh, K. ;

Bianchi, B. ;

McDonald, H. ;

Niforatos, W. ;

Neelands, T. R. ;

Moreland, R. B. ;

Decker, M. W. ;

Lee, C. -H. ;

Sullivan, J. P. ;

Faltynek, C. R. .

JOURNAL OF NEUROSCIENCE, 2006, 26 (37) :9385-9393

[6] Discovery of potent, orally available vanilloid receptor-1 antagonists.: Structure-activity relationship of N-aryl cinnamides [J].

Doherty, EM ;

Fotsch, C ;

Bo, YX ;

Chakrabarti, PP ;

Chen, N ;

Gavva, N ;

Han, NH ;

Kelly, MG ;

Kincaid, J ;

Klionsky, L ;

Liu, QY ;

Ognyanov, VI ;

Tamir, R ;

Wang, XH ;

Zhu, JW ;

Norman, NH ;

Treanor, JJS .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (01) :71-90

[7] Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists [J].

Drizin, I ;

Gomtsyan, A ;

Bayburt, EK ;

Schmidt, RG ;

Zheng, GZ ;

Perrier, RJ ;

DiDomenico, S ;

Koenig, JR ;

Turner, SC ;

Jinkerson, TK ;

Brown, BS ;

Keddy, RG ;

McDonald, HA ;

Honore, P ;

Wismer, CT ;

Marsh, KC ;

Wetter, JM ;

Polakowski, JS ;

Segreti, JA ;

Jarvis, MF ;

Faltynek, CR ;

Lee, CH .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (14) :4740-4749

[8] A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid [J].

El Kouhen, R ;

Surowy, CS ;

Bianchi, BR ;

Neelands, TR ;

McDonald, HA ;

Niforatos, W ;

Gomtsyan, A ;

Lee, CH ;

Honore, P ;

Sullivan, JP ;

Jarvis, MF ;

Faltynek, CR .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (01) :400-409

[9] Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade [J].

Gavva, Narender R. ;

Bannon, Anthony W. ;

Hovland, David N., Jr. ;

Lehto, Sonya G. ;

Klionsky, Lana ;

Surapaneni, Sekhar ;

Immke, David C. ;

Henley, Charles ;

Arik, Leyla ;

Bak, Annette ;

Davis, James ;

Ernst, Nadia ;

Hever, Gal ;

Kuang, Rongzhen ;

Shi, Licheng ;

Tamir, Rami ;

Wang, Jue ;

Wang, Weiya ;

Zajic, Gary ;

Zhu, Dawn ;

Norman, Mark H. ;

Louis, Jean-Claude ;

Magal, Ella ;

Treanor, James J. S. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 323 (01) :128-137

[10] The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation [J].

Gavva, Narender R. ;

Bannon, Anthony W. ;

Surapaneni, Sekhar ;

Hovland, David N., Jr. ;

Lehto, Sonya G. ;

Gore, Anu ;

Juan, Todd ;

Deng, Hong ;

Han, Bora ;

Klionsky, Lana ;

Kuang, Rongzhen ;

Le, April ;

Tamir, Rami ;

Wang, Jue ;

Youngblood, Brad ;

Zhu, Dawn ;

Norman, Mark H. ;

Magal, Ella ;

Treanor, James J. S. ;

Louis, Jean-Claude .

JOURNAL OF NEUROSCIENCE, 2007, 27 (13) :3366-3374

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