Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: Potent human histamine H-4 antagonists

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 lipophili...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 48; no. 26; pp. 8289 - 8298
Main Authors Venable, JD, Cai, H, Chai, WY, Dvorak, CA, Grice, CA, Jablonowski, JA, Shah, CR, Kwok, AK, Ly, KS, Pio, B, Wei, JM, Desai, PJ, Jiang, W, Nguyen, S, Ling, P, Wilson, SJ, Dunford, PJ, Thurmond, RL, Lovenberg, TW, Karlsson, L, Carruthers, NI, Edwards, JP
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 29.12.2005
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CELLS
HUMAN EOSINOPHILS
ACID
RECEPTOR ANTAGONISTS
RAT
CLONING
CHEMOTAXIS
Online AccessGet full text

Cover

More Information
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0502081