期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 6, 页码 2007-2012出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.01.065
关键词
Neurokinin-1 antagonist; Nuerokinin receptor; Substance P
Previous work on human NK1 (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50's of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. (C) 2010 Elsevier Ltd. All rights reserved.
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