期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 19, 页码 5684-5687出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.08.038
关键词
V1a antagonists; Triazoles; LiPE; Lead optimisation; Number of rotatable bonds
The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties. (C) 2011 Elsevier Ltd. All rights reserved.
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