Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists

  • J Med Chem. 2005 Dec 29;48(26):8289-98. doi: 10.1021/jm0502081.
Jennifer D Venable  1 ,  Hui Cai ,  Wenying Chai ,  Curt A Dvorak ,  Cheryl A Grice ,  Jill A Jablonowski ,  Chandra R Shah ,  Annette K Kwok ,  Kiev S Ly ,  Barbara Pio ,  Jianmei Wei ,  Pragnya J Desai ,  Wen Jiang ,  Steven Nguyen ,  Ping Ling ,  Sandy J Wilson ,  Paul J Dunford ,  Robin L Thurmond ,  Timothy W Lovenberg ,  Lars Karlsson ,  Nicholas I Carruthers ,  James P Edwards
Affiliations
  • 1. Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. [email protected]
PMID: 16366610 DOI: 10.1021/jm0502081
Abstract

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 [(3)H]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.

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