title: Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition.
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 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.
authors.affiliation: AstraZeneca CNS Discovery Research , 1800 Concord Pike, Wilmington, Delaware 19850, United States.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: Andrew
authors.initials: A
authors.lastname: Griffin
authors.forename: Steve
authors.initials: S
authors.lastname: Wesolowski
authors.forename: Denis
authors.initials: D
authors.lastname: Labrecque
authors.forename: Maxime C
authors.initials: MC
authors.lastname: Tremblay
authors.forename: Mark
authors.initials: M
authors.lastname: Sylvester
authors.forename: Russell
authors.initials: R
authors.lastname: Mauger
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Edwards
authors.forename: Scott R
authors.initials: SR
authors.lastname: Throner
authors.forename: James J
authors.initials: JJ
authors.lastname: Folmer
authors.forename: Joseph
authors.initials: J
authors.lastname: Cacciola
authors.forename: Clay
authors.initials: C
authors.lastname: Scott
authors.forename: Lois A
authors.initials: LA
authors.lastname: Lazor
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Pourashraf
authors.forename: Vijayaratnam
authors.initials: V
authors.lastname: Santhakumar
authors.forename: William M
authors.initials: WM
authors.lastname: Potts
authors.forename: Simon
authors.initials: S
authors.lastname: Sydserff
authors.forename: Pascall
authors.initials: P
authors.lastname: Giguère
authors.forename: Carine
authors.initials: C
authors.lastname: Lévesque
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dasser
authors.forename: Thierry
authors.initials: T
authors.lastname: Groblewski
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D002463:Cell Membrane Permeability; D003071:Cognition / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007858:Learning / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C587723:(4-isopropylpiperazin-1-yl)(6-(tetrahydro-2H-pyran-4-yl)-6-azaspiro(2.5)octan-1-yl)methanone; D001384:Azetidines; D003521:Cyclopropanes; D054828:Histamine H3 Antagonists; D010879:Piperazines; D010880:Piperidines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D013141:Spiro Compounds