Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists.
Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.
Berlin
Michael
M
Chemical Research, Cardiovascular/Metabolic Diseases and CNS Discovery, and Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, NJ 07033, USA. michael.berlin@merck.com
Lee
Yoon Joo
YJ
Boyce
Christopher W
CW
Wang
Yi
Y
Aslanian
Robert
R
McCormick
Kevin D
KD
Sorota
Steve
S
Williams
Shirley M
SM
West
Robert E
RE
Korfmacher
Walter
W
D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006633:Histamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D014508:Urea