Biphenyls as potent vitronectin receptor antagonists. Part 2: biphenylalanine ureas.
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).
Urbahns
Klaus
K
Institute of Medicinal Chemistry, Pharma Research Center, Bayer AG, D-42096 Wuppertal, Germany. klaus.urbahns.ku1@bayer.co.jp
Härter
Michael
M
Vaupel
Andrea
A
Albers
Markus
M
Schmidt
Delf
D
Brüggemeier
Ulf
U
Stelte-Ludwig
Beatrix
B
Gerdes
Christoph
C
Tsujishita
Hideki
H
D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D008024:Ligands; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
D001713:Biphenyl Compounds; D039302:Integrin alphaVbeta3; D008024:Ligands; D010649:Phenylalanine; D014508:Urea