title: Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.
abstract: The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.
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: 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: Youko
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 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; D001381:Azepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018004:Receptors, Bombesin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3
keywords: Bombesin receptor subtype-3 (BRS-3) agonists; Brain penetration; Diazepine