Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity.
The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.
Kameda
Minoru
M
Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Kobayashi
Kensuke
K
Ito
Hirokatsu
H
Miyazoe
Hiroshi
H
Tsujino
Toshiaki
T
Nakama
Chisato
C
Kawamoto
Hiroshi
H
Ando
Makoto
M
Ito
Sayaka
S
Suzuki
Tomoki
T
Kanno
Tetsuya
T
Tanaka
Takeshi
T
Tahara
Yoshio
Y
Tani
Takeshi
T
Tanaka
Sachiko
S
Tokita
Shigeru
S
Sato
Nagaaki
N
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D017476:Receptors, Neuropeptide Y; D011994:Recombinant Proteins; C097212:neuropeptide Y-Y1 receptor; C026805:2,4-diaminopyridine; D015761:4-Aminopyridine