title: Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect.
abstract: A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Company, Ltd., Okubo 3, Tsukuba 300-2611, Japan. nagaaki_sato@merck.com
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Shiho
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Jitsuoka
authors.forename: Keita
authors.initials: K
authors.lastname: Nagai
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Aya
authors.initials: A
authors.lastname: Sakuraba
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsuge
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kitazawa
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mashiko
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Moriya
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujino
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism; D004195:Disease Models, Animal; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009765:Obesity / Q000188:drug therapy*; D010599:Pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D048288:Imidazolines; C000606913:KCNH2 protein, human; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor