Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition

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• 作者：Dean G. Brown ; Peter R. Bernstein ; Andrew Griffin ; Steve Wesolowski ; Denis Labrecque ; Maxime C. Tremblay ; Mark Sylvester ; Russell Mauger ; Phillip D. Edwards ; Scott R. Throner ; James J. Folmer ; Joseph Cacciola ; Clay Scott ; Lois A. Lazor ; Mehrnaz Pourashraf ; Vijayaratnam Santhakumar ; William M. Potts ; Simon Sydserff ; Pascall Giguère ; Carine Lévesque ; Mohammed Dasser ; Thierry Groblewski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：733-758
• 全文大小：900K
• ISSN：1520-4804

文摘

A new series of potent and selective histamine-3 receptor (H₃R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H₃R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only 蟽2 (62% at 10 渭M). Compound 6s demonstrated free-plasma exposures above the IC₅₀ (50脳) with a brain-to-plasma ratio of 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H₃ receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.