Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Cornelison, Jeffery L.¹  Cato, Michael L.²  Johnson, Alyssa M.¹  D'Agostino, Emma H.²  Melchers, Diana³  Patel, Anamika B.²  Mays, Suzanne G.^2,4  Houtman, Rene³  Ortlund, Eric A.²  Jui, Nathan T.¹ 

[1] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[2] Emory Univ, Dept Biochem, Atlanta, GA 30322 USA

[3] Precis Med Lab, Pivot Pk,Antoni van Leeuwenhoek Bldg,Off 1131, NL-5349 AB Oss, Netherlands

[4] Ctr Genom Regulat, Calle Dr Aiguader 88, Barcelona 08003, Spain

关键词: Nuclear receptor;    LRH-1;    Photoredox;    Metabolic disease;    Agonist;   

DOI  :  10.1016/j.bmcl.2020.127293

来源: Elsevier

【 摘 要 】

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression.

【 授权许可】

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