Non-imidazole histamine H3 ligands, part IV: SAR of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives

Eur J Med Chem. 2009 Apr;44(4):1674-81. doi: 10.1016/j.ejmech.2008.09.019. Epub 2008 Sep 30.

Abstract

A series of 1-[[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propyl]piperazine derivatives have been prepared and in vitro tested as H(3)-receptor antagonists (the electrically evoked contraction of the guinea pig jejunum). It appeared that by comparison of homologous pairs the 1-[[2-thiazol-5-yl-(2-methyl-2-phenylalkylaminoethyl)]-4-n-propyl]piperazine derivatives (4c1-4c3) have slightly higher activity than their 1-[2-thiazol-5-yl-(2-methyl-2-alkylaminoethyl)]-4-n-propylpiperazine analogues (4b1-4b3). In the 2-methylalkylamide series (4a1-4a3) a somewhat lower activity was observed. The most potent compound of the series is the 1-[2-thiazol-5-yl-(2-methyl-2-phenylpropylaminoethyl)]-4-n-propylpiperazine (4c2) with pA(2)=8.27 (its alkyl analogue (4b2) showed pA(2)=7.53 and the corresponding amide (4a2) displayed pA(2)=7.36). Selected compounds (4b1, 4b2, 4c1 and 4c2) were also tested (in vitro) for H(1) antagonistic effects in vitro applying standard methods (guinea pig ileum). None showed any H(1) antagonistic activity (pA(2)<4).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Guinea Pigs
  • Histamine H1 Antagonists / chemical synthesis
  • Histamine H1 Antagonists / chemistry
  • Histamine H1 Antagonists / pharmacology
  • Histamine H3 Antagonists / chemical synthesis
  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / pharmacology*
  • Imidazoles / chemistry
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Male
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology*
  • Receptors, Histamine H3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Histamine H1 Antagonists
  • Histamine H3 Antagonists
  • Imidazoles
  • Piperazines
  • Receptors, Histamine H3
  • Piperazine
  • imidazole