Discovery of substituted benzyl tetrazoles as histamine H3 receptor antagonists.
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.
Davenport
Adam J
AJ
Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, United Kingdom. Adam.Davenport@evotec.com
Stimson
Christopher C
CC
Corsi
Massimo
M
Vaidya
Darshan
D
Glenn
Edward
E
Jones
Timothy D
TD
Bailey
Sarah
S
Gemkow
Mark J
MJ
Fritz
Ulrike
U
Hallett
David J
DJ
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*
D054828:Histamine H3 Antagonists; D013777:Tetrazoles