Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II

Stefanie Flohr, Michael Kurz, Evi Kostenis, Alexandre Brkovich, Alain Fournier, Thomas Klabunde
Journal of Medicinal Chemistry 2002 April 25, 45 (9): 1799-805
The vasoactive cyclic 11-amino acid peptide urotensin II (U-II) has recently been discovered as the endogenous ligand of the orphan G-protein-coupled receptor GPR14. As U-II might be involved in the regulation of cardiovascular homeostasis and pathology, a nonpeptidic GPR14/U-II antagonist is of considerable basic and therapeutic interest. We have performed structure-activity relationship studies on U-II by investigating 25 peptide analogues to mobilize intracellular calcium in GPR14-transfected CHO cells, demonstrating that only the side chains of the residues Trp-7, Lys-8, and Tyr-9 are required for receptor recognition and activation. The solution structure of U-II derived by nuclear magnetic resonance has served as a structural template for a three-dimensional three point pharmacophore query for the virtual screening of the Aventis compound repository for nonpeptidic U-II receptor antagonists. Highly active lead compounds of six different scaffold classes could be identified, antagonizing the biological activity of U-II in vitro. The most potent compound identified by the virtual screening approach, 1-(3-carbamimidoyl-benzyl)-4-methyl-1H-indole-2-carboxylic acid (naphthalen-1-ylmethyl)amide, reveals an IC(50) of 400 nM in a functional fluorometric imaging plate reader assay and constitutes a promising lead.


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