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

…, D Labrecque, MC Tremblay, M Sylvester…

Index: Brown, Dean G.; Bernstein, Peter R.; Griffin, Andrew; Wesolowski, Steve; Labrecque, Denis; Tremblay, Maxime C.; Sylvester, Mark; Mauger, Russell; Edwards, Phillip D.; Throner, Scott R.; Folmer, James J.; Cacciola, Joseph; Scott, Clay; Lazor, Lois A.; Pourashraf, Mehrnaz; Santhakumar, Vijayaratnam; Potts, William M.; Sydserff, Simon; Giguere, Pascall; Levesque, Carine; Dasser, Mohammed; Groblewski, Thierry Journal of Medicinal Chemistry, 2014 , vol. 57, # 3 p. 733 - 758

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Citation Number: 7

Abstract

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 σ2 (62% at 10 μM). Compound ...