title: Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kameda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazoe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsujino
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Tomoki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kanno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tani
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: 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
chemical_list: 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