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Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists |
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| 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 |
| Institution: | a Ligand Pharmaceuticals, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA b Department of Chemistry, MSD, Newhouse, Lanarkshire ML1 5SH, UK c Department of Pharmacology, MSD, Newhouse, Lanarkshire ML1 5SH, UK d Department of Molecular Pharmacology, MSD, Newhouse, Lanarkshire ML1 5SH, UK e Department of Clinical Research and Development, MSD, 5340BH Oss, The Netherlands |
| Abstract: | 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. |
| Keywords: | Vasopressin HPA axis |
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