2. Academic Validation
  3. Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors

Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors

  • Bioorg Med Chem Lett. 2008 Feb 1;18(3):1151-6. doi: 10.1016/j.bmcl.2007.11.124.
William K C Park 1,  Robert M Kennedy,  Scott D Larsen,  Steve Miller,  Bruce D Roth,  Yuntao Song,  Bruce A Steinbaugh,  Kevin Sun,  Bradley D Tait,  Mark C Kowala,  Bharat K Trivedi,  Bruce Auerbach,  Valerie Askew,  Lisa Dillon,  Jeffrey C Hanselman,  Zhiwu Lin,  Gina H Lu,  Andrew Robertson,  Catherine Sekerke
Affiliations

Affiliation

  • 1 Department of Chemistry, CVMED, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI, USA. wkcpark@gmail.com
PMID: 18155906 DOI: 10.1016/j.bmcl.2007.11.124
Abstract

4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing Cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.

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