title: 2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.
abstract: New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: takahashi.bitoku.cz@asubio.co.jp.
authors.forename: Bitoku
authors.initials: B
authors.lastname: Takahashi
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Funami
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Iwaki
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruoka
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Nagahira
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kamiide
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Matsuo
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Muto
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Annoura
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects; D015195:Drug Design; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D054440:Receptors, Ghrelin; D009536:Niacinamide
keywords: Anti-obesity; GhrelinR; Inverse agonist; Nicotinamide