Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity.
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.
Schnatbaum
Karsten
K
Jerini AG, Invalidenstrasse 130, 10115 Berlin, Germany. schnatbaum@jerini.de
Locardi
Elsa
E
Scharn
Dirk
D
Richter
Uwe
U
Hawlisch
Heiko
H
Knolle
Jochen
J
Polakowski
Thomas
T
D000818:Animals; D000936:Antigen-Antibody Complex / Q000009:adverse effects; D004195:Disease Models, Animal; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000936:Antigen-Antibody Complex; D009842:Oligopeptides; D044087:Receptor, Anaphylatoxin C5a