2. Academic Validation
  3. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ

Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ

  • Bioorg Med Chem Lett. 2015 Jan 15;25(2):372-7. doi: 10.1016/j.bmcl.2014.11.029.
Ellen Kick 1,  Richard Martin 2,  Yinong Xie 2,  Brenton Flatt 2,  Edwin Schweiger 2,  Tie-Lin Wang 2,  Brett Busch 2,  Michael Nyman 2,  Xiao-Hui Gu 2,  Grace Yan 2,  Brandee Wagner 2,  Max Nanao 2,  Lam Nguyen 2,  Thomas Stout 2,  Artur Plonowski 2,  Ira Schulman 2,  Jacek Ostrowski 3,  Todd Kirchgessner 3,  Ruth Wexler 4,  Raju Mohan 2
Affiliations

Affiliations

  • 1 Discovery Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: ellen.kick@bms.com.
  • 2 Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
  • 3 Cardiovascular Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
  • 4 Discovery Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
PMID: 25435151 DOI: 10.1016/j.bmcl.2014.11.029
Abstract

A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.

Keywords

ABCA1; LXR; Liver X Receptor; Nuclear hormone receptor; Partial agonist.

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