title: Discovery of substituted benzyl tetrazoles as histamine H3 receptor antagonists.
abstract: A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure-activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t(1/2)>60 min), minimal CYP inhibition (IC(50)>50 microM) and high cell permeability (Caco-2 P(app) >20x10(-6) cm/s) identified several compounds with drug-like properties.
authors.affiliation: Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, United Kingdom. Adam.Davenport@evotec.com
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Davenport
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Stimson
authors.forename: Massimo
authors.initials: M
authors.lastname: Corsi
authors.forename: Darshan
authors.initials: D
authors.lastname: Vaidya
authors.forename: Edward
authors.initials: E
authors.lastname: Glenn
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Jones
authors.forename: Sarah
authors.initials: S
authors.lastname: Bailey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gemkow
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fritz
authors.forename: David J
authors.initials: DJ
authors.lastname: Hallett
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D055808:Drug Discovery; D006207:Half-Life; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D054828:Histamine H3 Antagonists; D013777:Tetrazoles