Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides:: Potent human histamine H4 antagonists

被引：105

作者：

Venable, JD ^{[1
]}

Cai, H ^{[1
]}

Chai, WY ^{[1
]}

Dvorak, CA ^{[1
]}

Grice, CA ^{[1
]}

Jablonowski, JA ^{[1
]}

Shah, CR ^{[1
]}

Kwok, AK ^{[1
]}

Ly, KS ^{[1
]}

Pio, B ^{[1
]}

Wei, JM ^{[1
]}

Desai, PJ ^{[1
]}

Jiang, W ^{[1
]}

Nguyen, S ^{[1
]}

Ling, P ^{[1
]}

Wilson, SJ ^{[1
]}

Dunford, PJ ^{[1
]}

Thurmond, RL ^{[1
]}

Lovenberg, TW ^{[1
]}

Karlsson, L ^{[1
]}

Carruthers, NI ^{[1
]}

Edwards, JP ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 26期

关键词：

D O I：

10.1021/jm0502081

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Three series of H-4 receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H-4 receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [H-3]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H-4 antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.

引用

页码：8289 / 8298

页数：10

共 35 条

[1]

ASH AS, 1966, BR J PHARM, V27

[2]

BARTHOLOMEW D, 1979, TETRAHEDRON LETT, P2827

[3] DEFINITION AND ANTAGONISM OF HISTAMINE H2-RECEPTORS [J].

BLACK, JW ;

PARSONS, EM ;

DURANT, CJ ;

DUNCAN, WAM ;

GANELLIN, CR .

NATURE, 1972, 236 (5347) :385-&

[4] Parallel synthesis and evaluation of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins defining the contribution of the DNA-binding domain [J].

Boger, DL ;

Schmitt, HW ;

Fink, BE ;

Hedrick, MP .

JOURNAL OF ORGANIC CHEMISTRY, 2001, 66 (20) :6654-6661

[5] REACTIONS OF HYDROXYLAMINES WITH ETHYL CYANOFORMATE - PREPARATION OF AMINONITRONES AND THEIR SYNTHETIC APPLICATIONS [J].

BRANCO, PS ;

PRABHAKAR, S ;

LOBO, AM ;

WILLIAMS, DJ .

TETRAHEDRON, 1992, 48 (30) :6335-6360

[6] Histamine induces cytoskeletal changes in human eosinophils via the H4 receptor [J].

Buckland, KF ;

Williams, TJ ;

Conroy, DM .

BRITISH JOURNAL OF PHARMACOLOGY, 2003, 140 (06) :1117-1127

[7]

CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099

[8] The preparation and reactions of 2-benzimidazolecarboxylic acid and 2-benzimidazoleacetic acid [J].

Copeland, RAB ;

Day, AR .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1943, 65 :1072-1075

[9] PHOTOCHEMISTRY OF HETEROCYCLICS .3. PHOTOLYSIS OF VARIOUS 2-SUBSTITUTED BENZIMIDAZOLES [J].

CRANK, G ;

MURSYIDI, A .

AUSTRALIAN JOURNAL OF CHEMISTRY, 1982, 35 (04) :775-784

[10]

DETTY MR, 1995, HETEROCYCLES, V40, P925

← 1 2 3 4 →