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

Autor: Park WK; Department of Chemistry, CVMED, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI, USA. wkcpark@gmail.com, Kennedy RM, Larsen SD, Miller S, Roth BD, Song Y, Steinbaugh BA, Sun K, Tait BD, Kowala MC, Trivedi BK, Auerbach B, Askew V, Dillon L, Hanselman JC, Lin Z, Lu GH, Robertson A, Sekerke C
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Feb 01; Vol. 18 (3), pp. 1151-6. Date of Electronic Publication: 2007 Dec 05.
DOI: 10.1016/j.bmcl.2007.11.124
Abstrakt: 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.
Databáze: MEDLINE
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