title: Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model.
abstract: A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 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 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 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 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 650-0047, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 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 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 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 650-0047, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kanki
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Igawa
authors.affiliation: Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Muto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D054314:Drug Inverse Agonism; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D009765:Obesity / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D054440:Receptors, Ghrelin; D009536:Niacinamide
keywords: 2-Aminoalkyl nicotinamide; GhrelinR; Inverse agonist; Obesity