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We describe the discovery of analog 15 (FLG249), which is an orally active and nonsteroidal farnesoid X receptor (FXR) antagonist in mice with unique profiles, such as a propensity for ileum distribution and the significant control in the expression level of three FXR target genes in mouse ileum. Key design features incorporated in 15 were the introduction of metabolically stable groups in potent and metabolically labile antagonist 9. Our pursuit ultimately identified FXR antagonist 15, which has enabled its assessment in a drug discov
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