Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases
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.
Sun, Shaoyi,Zhang, Zaihui,Kodumuru, Vishnumurthy,Pokrovskaia, Natalia,Fonarev, Julia,Jia, Qi,Leung, Po-Yee,Tran, Jennifer,Ratkay, Leslie G.,McLaren, David G.,Radomski, Chris,Chowdhury, Sultan,Fu, Jianmin,Hubbard, Brian,Winther, Michael D.,Dales, Natalie A.
p. 520 - 525
(2014/01/23)
2-SUBSTITUTED 5-MEMBERED HETEROCYCLES AS SCD INHIBITORS
The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed
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Page/Page column 77
(2008/12/06)
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