Markus Albers

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).

Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent α4β1 integrin antagonists

Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.

Discovery and evaluation of terephthalic acid derivatives as potent α4β1 integrin antagonists

Terephthalic acid based derivatives containing β- and γ-amino acid residues were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the very late antigen 4 (VLA-4) and the vascular cell adhesion molecule 1 (VCAM-1). The compounds 2, 10–12, 14, and 16–17 inhibited the adhesion in a cell based assay in the low and sub micromolar range.