Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity

Karsten Schnatbaum; Elsa Locardi; Dirk Scharn; Uwe Richter; Heiko Hawlisch; Jochen Knolle; Thomas Polakowski

doi:10.1016/j.bmcl.2006.07.036

Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. doi: 10.1016/j.bmcl.2006.07.036. Epub 2006 Jul 28.

Authors

Karsten Schnatbaum¹, Elsa Locardi, Dirk Scharn, Uwe Richter, Heiko Hawlisch, Jochen Knolle, Thomas Polakowski

Affiliation

¹ Jerini AG, Invalidenstrasse 130, 10115 Berlin, Germany. schnatbaum@jerini.de

PMID: 16876401
DOI: 10.1016/j.bmcl.2006.07.036

Abstract

A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids with hydrophobic side chains is presented. Systematic optimization of the first hits led to JPE1375 (36), which was intensively characterized in vitro and in vivo. Compound 36 exhibits high microsomal stability and receptor specificity and is highly active in an immune complex mediated peritonitis model (reverse passive Arthus reaction) in mice.

MeSH terms

Animals
Antigen-Antibody Complex / adverse effects
Disease Models, Animal
Hydrophobic and Hydrophilic Interactions
Inhibitory Concentration 50
Mice
Molecular Mimicry
Oligopeptides / chemistry*
Oligopeptides / pharmacology*
Peritonitis / chemically induced
Peritonitis / drug therapy*
Receptor, Anaphylatoxin C5a / antagonists & inhibitors*
Structure-Activity Relationship
Substrate Specificity

Substances

Antigen-Antibody Complex
Oligopeptides
Receptor, Anaphylatoxin C5a