Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists

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• 作者：Yohei Kiyotsuka^a ; ^{kiyotsuka.yohei.kv@daiichisankyo.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Kousei Shimada^a ; Shozo Kobayashi^a ; Masanori Suzuki^a ; Mayuko Akiu^a ; Masayoshi Asano^a ; Yoshitaka Sogawa^b ; Takashi Hara^b ; Masahiro Konishi^b ; Rie Abe-Ohya^b ; Masanori Izumi^b ; Yoko Nagai^c ; Kazuhiro Yoshida^c ; Yasuyuki Abe^d ; Hideo Takamori^d ; Hisashi Takahashi^a
• 关键词：Anti-obesity ; Antedrug ; Bombesin receptor subtype-3 (BRS-3) ; Brain penetration ; Imidazole
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：26
• 期：17
• 页码：4205-4210
• 全文大小：2117 K

文摘

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.