Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition
| Autor: | Pourashraf Mehrnaz, Russell C. Mauger, Steve Wesolowski, Phillip D Edwards, Simon Sydserff, Carine Lévesque, Maxime Tremblay, Thierry Groblewski, Vijayaratnam Santhakumar, Lois Ann Lazor, Bernstein Peter Robert, James Folmer, Pascall Giguère, William Potts, Denis Labrecque, Scott Throner, Joseph Cacciola, Mark Sylvester, Mohammed Dasser, Clay W Scott, Dean G. Brown, Andrew Griffin |
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| Rok vydání: | 2014 |
| Předmět: |
Cyclopropanes
Male Models Molecular Cell Membrane Permeability Pyrrolidines medicine.drug_class Carboxamide CHO Cells Pharmacology Piperazines Madin Darby Canine Kidney Cells Rats Sprague-Dawley chemistry.chemical_compound Mice Structure-Activity Relationship Cognition Cricetulus Dogs Piperidines In vivo Cricetinae Drug Discovery medicine Structure–activity relationship Animals Humans Learning Receptors Histamine H3 Spiro Compounds Receptor IC50 Chemistry Recognition Psychology Stereoisomerism Rats Piperazine Microsomes Liver Molecular Medicine Azetidines Histamine H3 receptor Histamine Histamine H3 Antagonists |
| Zdroj: | Journal of medicinal chemistry. 57(3) |
| ISSN: | 1520-4804 |
| Popis: | 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 6s demonstrated free-plasma exposures above the IC50 (∼50×) 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. |
| Databáze: | OpenAIRE |
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