Scaffold Hopping Provides Liver X Receptor Agonist With Preference for the β Subtype

The liver X receptor is a promising target for diseases with dysregulated cholesterol levels. In addition to enhanced reverse cholesterol transport, however, LXR activation induces hepatic lipogenesis. Since the subtype LXRα is dominant in the liver, one strategy to overcome this is the development of LXRβ-selective agonists. We optimized the reported compound 2 with efficacy-based preference for LXRβ by scaffold hopping to enhance potency and selectivity. Among the four different scaffolds, which were obtained from computer-assisted design and subsequent synthesis, compound 7 emerged as the most promising scaffold. The spiro[indan-1,4'-piperidine] scaffold of 7 demonstrated superior pharmacokinetic and pharmacodynamic properties, warranting its further investigation towards a pharmacological tool compound.