Synthesis, structure–activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H3 receptor inverse agonists

Abstract

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H3 receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H3 inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H3 receptor was fully occupied.