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2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists

2007; Elsevier BV; Volume: 17; Issue: 16 Linguagem: Inglês

10.1016/j.bmcl.2007.06.017

1464-3405

Sunil M. Kher, Kirk Lake, Ila Sircar, Madhavi Pannala, Farid Bakir, James Zapf, Kui Xu, Shaohui Zhang, Juping Liu, Lisa Morera, Naoki Sakurai, R M Jack, Jie‐Fei Cheng,

Sphingolipid Metabolism and Signaling

Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.