Aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists--Increasing selectivity over hERG.
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.
Meyers
Kenneth M
KM
Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45039, USA.
Méndez-Andino
José L
JL
Colson
Anny-Odile
AO
Warshakoon
Namal C
NC
Wos
John A
JA
Mitchell
Maria C
MC
Hodge
Karen M
KM
Howard
Jeremy M
JM
Ackley
David C
DC
Holbert
Jerry K
JK
Mittelstadt
Scott W
SW
Dowty
Martin E
ME
Obringer
Cindy M
CM
Reizes
Ofer
O
Hu
X Eric
XE
D000818:Animals; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D015431:Weight Loss / Q000187:drug effects
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; C000606913:KCNH2 protein, human; C103263:MCHR1 protein, human; D009281:Naphthalenes; D010879:Piperazines; D026902:Potassium Channel Blockers; D017481:Receptors, Somatostatin; C518531:aminomethyl tetrahydronaphthalene ketopiperazine