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 (â¼50×) with a brain-to-plasma ratio of â¼3 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.
Subject(s)
Cognition/drug effects , Cyclopropanes/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/metabolism , Spiro Compounds/chemical synthesis , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Azetidines/pharmacology , CHO Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Dogs , Histamine H3 Antagonists/pharmacokinetics , Histamine H3 Antagonists/pharmacology , Humans , Learning/drug effects , Madin Darby Canine Kidney Cells , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/genetics , Recognition, Psychology/drug effects , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The stereoselective acetylation of meso-2,2-dimethyl-1,3-cyclohexanediol by vinyl acetate in the presence of three lipases gave the (1R,3S)-monoester in high enantiomeric excess (ee > or = 98%). The hydrolysis of the corresponding meso-diacetate in the presence of Candida antarctica lipase in phosphate buffer provided the opposite enantiomer. Optically active monoacetates were converted to both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile chiral building block.
