title: Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.
abstract: Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: matsufuji.tetsuyoshi.nf@daiichisankyo.co.jp.
authors.forename: Tetsuyoshi
authors.initials: T
authors.lastname: Matsufuji
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kousei
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Arita
authors.affiliation: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.affiliation: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Abe-Ohya
authors.affiliation: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Izumi
authors.affiliation: Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD NOVARE Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004341:Drug Evaluation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D018004:Receptors, Bombesin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001381:Azepines; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3
keywords: Antedrug; Anti-obesity; Bombesin receptor subtype-3 (BRS-3); Brain penetration; Diazepine