Design and synthesis of 1-indol-1-yl-propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha

Joachim Ludwig; Stefanie Bovens; Carsten Brauch; Alwine Schulze Elfringhoff; Matthias Lehr

doi:10.1021/jm051243a

Design and synthesis of 1-indol-1-yl-propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha

J Med Chem. 2006 Apr 20;49(8):2611-20. doi: 10.1021/jm051243a.

Authors

Joachim Ludwig¹, Stefanie Bovens, Carsten Brauch, Alwine Schulze Elfringhoff, Matthias Lehr

Affiliation

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

PMID: 16610804
DOI: 10.1021/jm051243a

Abstract

The synthesis and structure-activity relationship study of a series of 1-indol-1-yl-3-phenoxypropan-2-one inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) are described. The compounds were evaluated in a vesicle assay with isolated cPLA(2)alpha and in cellular assays with intact human platelets. Systematic variation led to 3-methylhydrogen 1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate (57), which revealed the highest activity against the isolated enzyme. With an IC(50) value of 4.3 nM in this assay, it is one of the most potent in vitro cPLA(2)alpha inhibitors known today.

MeSH terms

Blood Platelets / drug effects
Blood Platelets / enzymology
Cytosol / drug effects
Cytosol / enzymology
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Group IV Phospholipases A2
Humans
Indoles* / chemical synthesis
Indoles* / chemistry
Indoles* / pharmacology
Ketones* / chemical synthesis
Ketones* / chemistry
Ketones* / pharmacology
Molecular Structure
Phospholipases A / antagonists & inhibitors*
Propane / analogs & derivatives
Propane / chemical synthesis*
Propane / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Indoles
Ketones
Phospholipases A
Group IV Phospholipases A2
Propane