Antileukotrienic phenethylamido derivatives of arylalkanoic acids in the treatment of ulcerative colitis

Eur J Med Chem. 2009 Jan;44(1):332-44. doi: 10.1016/j.ejmech.2008.02.030. Epub 2008 Mar 7.

Abstract

A series of arylalkanoic acid derivatives bearing methyl(phenethyl)amino groups were prepared and their inhibition of LTB(4) biosynthesis was evaluated. Regression analysis showed the slightly different parabolic dependences of this activity on lipophilicity of alpha-methyl and alpha-unsubstituted alkanoic acid derivatives. The relationship derived for alpha-unsubstituted alkanoic acids was extended by previously prepared group of similar derivatives of arylacetic acids without any change of regression coefficients and statistical criteria. It was concluded that the most active compounds belong to 2-arylpropanoic acid derivatives with lipophilicity close to logP(opt) (=6.97). But generally, the structural changes in the acidic part of compounds under study did not yield the substantial improvement of LTB(4) biosynthesis inhibition in comparison with the previously prepared series of derivatives IV. The anti-inflammatory effect of the compounds under study was evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. From 12 evaluated compounds, 4 compounds are more active in UC inhibition than the standard sulfasalazine but it can be stated that the change of connecting chain between aromatic ring and carboxyl did not bring about the important improvement of this activity in comparison with previous derivatives of arylacetic acids. Possible relation between LTB(4) biosynthesis inhibition and ulcerative colitis is seriously broken by the compound 8a with carbonyl as the additional functional group on the connecting chain between carboxyl and aromatic ring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / pharmacology
  • Carboxylic Acids
  • Cells, Cultured
  • Colitis, Ulcerative / drug therapy*
  • Gastrointestinal Agents / chemical synthesis
  • Gastrointestinal Agents / pharmacology
  • Hydrocarbons, Aromatic / chemical synthesis*
  • Hydrocarbons, Aromatic / pharmacology
  • Inflammation / drug therapy
  • Leukocytes
  • Quantitative Structure-Activity Relationship
  • Rats
  • Receptors, Leukotriene B4 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Carboxylic Acids
  • Gastrointestinal Agents
  • Hydrocarbons, Aromatic
  • Receptors, Leukotriene B4