4-phenoxypiperidine pyridazin-3-one histamine H(3) receptor inverse agonists demonstrating potent and robust wake promoting activity

Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.     

Synthesis and evaluation of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues as histamine-3 receptor antagonists

A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.     

Binding of dexetimide and levetimide to [3H](+)pentazocine- and [3H]1,3-di(2-tolyl)guanidine-defined sigma recognition sites.

The potent antimuscarinic benzetimide and its resolved stereoisomers dexetimide and levetimide were tested for their affinities at sigma sites labelled by [3H](+)pentazocine or [3H]1,3-di(2-tolyl)guanidine. Levetimide was a potent and stereoselective inhibitor of [3H](+)pentazocine binding, with a Ki of 2.2 nM, while dexetimide was nine-fold less potent (Ki = 19 nM). Dexetimide and levetimide potently inhibited [3H]DTG binding although without stereoselectivity (Ki values of 65 and 103 nM, respectively). Levetimide may be a useful tool with which to investigate sigma recognition sites and sigma subtypes.