Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V₁b receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 6; pp. 1871 - 1875
• Main Authors: Napier, Susan E, Letourneau, Jeffrey J, Ansari, Nasrin, Auld, Douglas S, Baker, James, Best, Stuart, Campbell-Wan, Leigh, Chan, Jui-Hsiang, Craighead, Mark, Desai, Hema, Goan, Katharine A, Ho, Koc-Kan, Hulskotte, Ellen G.J, MacSweeney, Cliona P, Milne, Rachel, Morphy, J. Richard, Neagu, Irina, Ohlmeyer, Michael H.J, Peeters, Ard W.M.M, Presland, Jeremy, Riviello, Chris, Ruigt, Ge S.F, Thomson, Fiona J, Zanetakos, Heather A, Zhao, Jiuqiao, Webb, Maria L
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2011; Elsevier
• Subjects: acetamides; Animals; antagonists; Antidiuretic Hormone Receptor Antagonists; Biological and medical sciences; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; oxytocin; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacokinetics; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Rats; receptors; Structure-Activity Relationship; structure-activity relationships; vasopressin; V1b vasopressin receptor; Intravenous administration; Rat; Hypothalamohypophysoadrenal axis; Quinazoline derivatives; Rodentia; Oral administration; HPA axis; Vasopressin; Vertebrata; Mammalia; Structure activity relation; Animal; Antagonist; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.081

Synthesis and structure–activity relationships (SAR) of a novel series of vasopressin V₁b (V₃) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V₁b receptor and good selectivity with respect to related receptors V₁ₐ, V₂ and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.