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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 18; pp. 5394 - 5397
• Main Authors: Letourneau, Jeffrey J., Riviello, Christopher M., Li, Hong, Cole, Andrew G., Ho, Koc-Kan, Zanetakos, Heather A., Desai, Hema, Zhao, Jiuqiao, Auld, Douglas S., Napier, Susan E., Thomson, Fiona J., Goan, Katharine A., Morphy, J. Richard, Ohlmeyer, Michael H.J., Webb, Maria L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2010; Elsevier
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Animals; Antagonist; Antagonists; Antidiuretic Hormone Receptor Antagonists; Biological and medical sciences; Depressive Disorder - drug therapy; HPA axis; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinone; Rats; Receptors, Vasopressin - metabolism; Structure-Activity Relationship; Vasopressin (V1b) receptor; HPA axis; Antagonist; Quinazolinone; Vasopressin (V1b) receptor; Human; V1b vasopressin receptor; Cyclopropane derivatives; Rat; Hypothalamohypophysoadrenal axis; Nitrogen heterocycle; Rodentia; Lactam; Aminoether; Morpholine derivatives; In vitro; Vertebrata; Mammalia; Structure activity relation; Animal; Affinity; Carboxamide; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.118

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 (IC 50 = 0.20 μM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC 50 = 0.31 μM) and 24 (IC 50 = 0.12 μM) with improved drug-like characteristics.