α-Methylation at benzylic fragment of N-aryl-N′-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model

被引：30

作者：

Gomtsyan, Arthur ^{[1
]}

Bayburt, Erol K. ^{[1
]}

Keddy, Ryan ^{[1
]}

Turner, Sean C. ^{[1
]}

Jinkerson, Tammie K. ^{[1
]}

Didomenico, Stanley ^{[1
]}

Perner, Richard J. ^{[1
]}

Koenig, John R. ^{[1
]}

Drizin, Irene ^{[1
]}

McDonald, Heath A. ^{[1
]}

Surowy, Carol S. ^{[1
]}

Honore, Prisca ^{[1
]}

Mikusa, Joe ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Wetter, Jill M. ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Lee, Chih-Hung ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 14期

关键词：

TRPV1; antagonist; urea; pain;

D O I：

10.1016/j.bmcl.2007.04.105

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR studies for N-aryl-N '-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：3894 / 3899

页数：6

共 16 条

[1] SYNTHESIS AND REACTIVITY OF NITROINDAZOLES [J].

BENCHIDMI, M ;

BOUCHET, P ;

LAZARO, R .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1979, 16 (08) :1599-1603

[2] CHEMISTRY OF O-DI-T-BUTYLBENZENE [J].

BURGSTAHLER, AW ;

ABDELRAHMAN, MO ;

CHIEN, P .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1964, 86 (23) :5281-&

[3] HIGHLY ENANTIOSELECTIVE BORANE REDUCTION OF KETONES CATALYZED BY CHIRAL OXAZABOROLIDINES - MECHANISM AND SYNTHETIC IMPLICATIONS [J].

COREY, EJ ;

BAKSHI, RK ;

SHIBATA, S .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1987, 109 (18) :5551-5553

[4] Biochemical pharmacology of the vanilloid receptor TRPV1 - An update [J].

Cortright, DN ;

Szallasi, A .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2004, 271 (10) :1814-1819

[5] THE ENANTIOSELECTIVE SYNTHESIS OF THE POTENT DOPAMINE D1 AGONIST (1R,3S)-3-(1'-ADAMANTYL)-1-(AMINOMETHYL)-3,4-DIHYDRO-5,6-DIHYDROXY-1H-2-BENZOPYRAN (A77636) [J].

DENINNO, MP ;

PERNER, RJ ;

MORTON, HE ;

DIDOMENICO, S .

JOURNAL OF ORGANIC CHEMISTRY, 1992, 57 (26) :7115-7118

[6] 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

[7] 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

[8] Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: Structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties [J].

Gomtsyan, A ;

Bayburt, EK ;

Schmidt, RG ;

Zheng, GZ ;

Perner, RJ ;

Didomenico, S ;

Koenig, JR ;

Turner, S ;

Jinkerson, T ;

Drizin, I ;

Hannick, SM ;

Macri, BS ;

McDonald, HA ;

Honore, P ;

Wismer, CT ;

Marsh, KC ;

Wetter, J ;

Stewart, KD ;

Oie, T ;

Jarvis, MF ;

Surowy, CS ;

Faltynek, CR ;

Lee, CH .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (03) :744-752

[9] A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats [J].

Honore, P ;

Wismer, CT ;

Mikusa, J ;

Zhu, CZ ;

Zhong, CM ;

Gauvin, DM ;

Gomtsyan, A ;

El Kouhen, R ;

Lee, CH ;

Marsh, K ;

Sullivan, JP ;

Faltynek, CR ;

Jarvis, MF .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (01) :410-421

[10] The TRPV1 receptor and nociception [J].

Immke, David C. ;

Gavva, Narender R. .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2006, 17 (05) :582-591

← 1 2 →