title: Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists.
abstract: Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion.
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: kiyotsuka.yohei.kv@daiichisankyo.co.jp.
authors: Yohei
authors: Y
authors: Kiyotsuka
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Kousei
authors: K
authors: Shimada
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Shozo
authors: S
authors: Kobayashi
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masanori
authors: M
authors: Suzuki
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Mayuko
authors: M
authors: Akiu
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masayoshi
authors: M
authors: Asano
authors: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Yoshitaka
authors: Y
authors: Sogawa
authors: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Takashi
authors: T
authors: Hara
authors: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masahiro
authors: M
authors: Konishi
authors: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Rie
authors: R
authors: Abe-Ohya
authors: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masanori
authors: M
authors: Izumi
authors: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Yoko
authors: Y
authors: Nagai
authors: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Kazuhiro
authors: K
authors: Yoshida
authors: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors: Yasuyuki
authors: Y
authors: Abe
authors: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors: Hideo
authors: H
authors: Takamori
authors: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Hisashi
authors: H
authors: Takahashi
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004435:Eating / Q000187:drug effects; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018004:Receptors, Bombesin / Q000819:agonists* / Q000378:metabolism
chemical_list: D000085:Acetates; D019440:Anti-Obesity Agents; D006574:Heterocyclic Compounds, 2-Ring; D007093:Imidazoles; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; C029899:imidazole
keywords: Antedrug; Anti-obesity; Bombesin receptor subtype-3 (BRS-3); Brain penetration; Imidazole