2. Academic Validation
  3. Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach

  • Bioorg Med Chem. 2015 Jan 1;23(1):89-104. doi: 10.1016/j.bmc.2014.11.018.
Tetsuyoshi Matsufuji 1,  Kousei Shimada 2,  Shozo Kobayashi 2,  Masanori Ichikawa 2,  Asuka Kawamura 2,  Teppei Fujimoto 2,  Tsuyoshi Arita 2,  Takashi Hara 3,  Masahiro Konishi 3,  Rie Abe-Ohya 3,  Masanori Izumi 3,  Yoshitaka Sogawa 3,  Yoko Nagai 4,  Kazuhiro Yoshida 4,  Yasuyuki Abe 5,  Takako Kimura 6,  Hisashi Takahashi 2
Affiliations

Affiliations

  • 1 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.
  • 2 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Cardiovascular Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 6 Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD NOVARE Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 25497965 DOI: 10.1016/j.bmc.2014.11.018
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.

Keywords

Antedrug; Anti-obesity; Bombesin receptor subtype-3 (BRS-3); Brain penetration; Diazepine.

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