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
  • 1. Department of Chemistry, CVMED, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI, USA. [email protected]
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.