Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

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• 作者：Shaoyi Sun ; Zaihui Zhang ; Vishnumurthy Kodumuru ; Natalia Pokrovskaia ; Julia Fonarev ; Qi Jia ; Po-Yee Leung ; Jennifer Tran ; Leslie G. Ratkay ; David G. McLaren ; Chris Radomski ; Sultan Chowdhury ; Jianmin Fu ; Brian Hubbard ; Michael D. Winther ; Natalie A. Dales
• 关键词：Stearoyl-CoA desaturase-1 ; SCD1 inhibitors ; Amide bioisosteres ; Thiazolylimidazolidinone ; Desaturation index
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 January, 2014
• 年：2014
• 卷：24
• 期：2
• 页码：520-525
• 全文大小：759 K

文摘

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC₅₀ of 4.5 mg/kg.