New Anthranilic Acid Based Antagonists with High Affinity and Selectivity for the Human Cholecystokinin Receptor 1 (hCCK1-R)

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• 作者：Michela V. Pavan ; Lucia Lassiani ; Federico Berti ; Giorgio Stefancich ; Alessia Ciogli ; Francesco Gasparrini ; Laura Mennuni ; Flora Ferrari ; Chantal Escrieut ; Esther Marco ; Francesco Makovec ; Daniel Fourmy ; Antonio Varnavas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5769-5785
• 全文大小：1253K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

The anthranilic acid diamides represent the most recent class of nonpeptide CCK₁ receptor (CCK₁-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK₁-R affinity and 15-fold for the human CCK₁-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK₁-R and was at least 400-fold selective for the CCK₁-R over the CCK₂-R. Molecular docking in the modeled CCK₁-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK₁-R antagonists.