The Liver X Receptor (LXR)-α and -β isoforms are nuclear transcription factors that regulate a number of genes involved in lipid metabolism e.g. the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is involved in the process of reverse cholesterol transport, where cholesterol is removed from plaques in the arterial wall, to form high density lipoproteins (HDL), which are transported to the liver for metabolism. As such, LXR agonists may offer therapeutic potential in the treatment of atherosclerosis.<br/>Our research program, aimed to use biostructural information to optimize a series of piperazine amide based LXR agonists. Compound 1 had low permeability (and low F%) and attempts were made to reduce the number of H-bond donors. Both the NH’s of the urea H-bonded to Glu103 of LXRα and replacing either with a CH<sub>2</sub> led to ≥10 fold decrease in activity (and improved permeability). An alternative strategy was to introduce a halogen atom ortho to the aromatic NH (e.g. F in compound 2) which gave a &gt;20 fold improvement in PAMPA permeability with comparable activity. Compound 2 was found to have an off target human acetylcholinesterase (hAChE) effect and SAR studies showed this was related to the t-butyl amide region. Attempts were made to alter this region and one approach was to hybridize with the literature LXR agonist T1317, which led to the potent LXR agonist 3, which was inactive at hAChE. Compound 3 suffered from poor solubility, and an isopropyl solvent molecule from a GW3965 structure, was inspiration to incorporate polar functionalities onto the alkyl group of the urea to give compounds like 4.

Biostructural optimisation of a piperazine amide based series of Liver X Receptor (LXR) agonists

256th National Meeting (2018)

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