title: Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor.
abstract: A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Company, Ltd, Okubo, Tsukuba, Japan. andoumkt@gmail.com
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagase
authors.forename: Keita
authors.initials: K
authors.lastname: Nagai
authors.forename: Shiho
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
authors.forename: Junko
authors.initials: J
authors.lastname: Ito
authors.forename: Mioko
authors.initials: M
authors.lastname: Hirayama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsushita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tadano
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujino
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C544487:1-(difluoromethyl)-5-((4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2(1H)-one; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019440:Anti-Obesity Agents; D048288:Imidazolines; D011728:Pyridones; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor