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Journals and Conferences
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust… (More)
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency… (More)
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.
In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an… (More)
A series of potent 5-hydroxytryptamine 6 (5-HT₆) receptor antagonists based on 1-thia-4,7-diaza-spiro[4.4]nonane-3,6-dione motif has been disclosed. Enantiomers of potent racemate compound 8a (K(i) = 26 nM) displayed difference in activity (K(i) of 15 nM versus 855 nM) signaling the influence of the stereochemistry of the chiral center on potency. In… (More)
A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating… (More)