Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists

The discovery, synthesis, and preliminary structure–activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS™ technology, had good activity in a V3 binding assay (IC50 = 0.20 μM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50 = 0.31 μM) and 24 (IC50 = 0.12 μM) with improved drug-like characteristics.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide