Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition.

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.

Chemoenzymatic synthesis of both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone.

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.