title: Synthesis and evaluation of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues as histamine-3 receptor antagonists.
abstract: 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.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nbecknell@cephalon.com
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Reddeppa Reddy
authors.initials: RR
authors.lastname: Dandu
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004347:Drug Interactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006633:Histamine Antagonists / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; C000606913:KCNH2 protein, human; D010880:Piperidines; D018100:Receptors, Histamine H3; D013141:Spiro Compounds