Novel small molecule bradykinin B1 receptor antagonists. Part 1: benzamides and semicarbazides.
The synthesis and SAR of two series of bradykinin B(1) receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.
Schaudt
Marco
M
Jerini AG, Invalidenstrasse 130, 10115 Berlin, Germany.
Locardi
Elsa
E
Zischinsky
Gunther
G
Stragies
Roland
R
Pfeifer
Jochen R
JR
Gibson
Christoph
C
Scharn
Dirk
D
Richter
Uwe
U
Kalkhof
Holger
H
Dinkel
Klaus
K
Schnatbaum
Karsten
K
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D018938:Caco-2 Cells; D006801:Humans; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D012663:Semicarbazides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D001549:Benzamides; D065169:Bradykinin B1 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D012663:Semicarbazides