Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Kiyotsuka, Yohei; Shimada, Kousei; Kobayashi, Shozo; Suzuki, Masanori; Akiu, Mayuko; Asano, Masayoshi; Sogawa, Yoshitaka; Hara, Takashi; Konishi, Masahiro; Abe-Ohya, Rie; Izumi, Masanori; Nagai, Yoko; Yoshida, Kazuhiro; Abe, Yasuyuki; Takamori, Hideo; Takahashi, Hisashi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4205
• Page End: 4210
• Publication Date: 2016-09-01
• Subjects: Anti-obesity -- Antedrug -- Bombesin receptor subtype-3 (BRS-3) -- Brain penetration -- Imidazole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.056
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Novel compounds based on1a 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 ester2b 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.