1-(2-Carboxyindol-5-yloxy)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: synthesis, biological activity, metabolic stability, and solubility

Alexandra Fritsche; Alwine Schulze Elfringhoff; Jörg Fabian; Matthias Lehr

doi:10.1016/j.bmc.2008.02.019

1-(2-Carboxyindol-5-yloxy)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: synthesis, biological activity, metabolic stability, and solubility

Bioorg Med Chem. 2008 Apr 1;16(7):3489-500. doi: 10.1016/j.bmc.2008.02.019. Epub 2008 Feb 13.

Authors

Alexandra Fritsche¹, Alwine Schulze Elfringhoff, Jörg Fabian, Matthias Lehr

Affiliation

¹ Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.

PMID: 18321717
DOI: 10.1016/j.bmc.2008.02.019

Abstract

Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) isolated from human platelets. In continuation of our attempts to develop novel cPLA(2)alpha inhibitors, a series of structurally related indole-2-carboxylic acids containing 3-aryloxy-2-oxopropoxy residues in position 5 were synthesized and tested for their cPLA(2)alpha-inhibitory potency. Furthermore, the thermodynamic solubility of these compounds and their metabolic stability against rat liver microsomes were evaluated.

MeSH terms

Blood Platelets / drug effects
Blood Platelets / enzymology
Chromatography, High Pressure Liquid
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Group IV Phospholipases A2 / antagonists & inhibitors*
Group IV Phospholipases A2 / metabolism*
Humans
Indoles / chemistry*
Molecular Structure
Propionates / chemical synthesis*
Propionates / chemistry
Propionates / metabolism
Propionates / pharmacology*
Solubility
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Indoles
Propionates
Group IV Phospholipases A2