title: Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors.
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.
authors.affiliation: Department of Chemistry, CVMED, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI, USA. wkcpark@gmail.com
authors.forename: William K C
authors.initials: WK
authors.lastname: Park
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kennedy
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Steve
authors.initials: S
authors.lastname: Miller
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Roth
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Song
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Steinbaugh
authors.forename: Kevin
authors.initials: K
authors.lastname: Sun
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Tait
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: Bruce
authors.initials: B
authors.lastname: Auerbach
authors.forename: Valerie
authors.initials: V
authors.lastname: Askew
authors.forename: Lisa
authors.initials: L
authors.lastname: Dillon
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Lin
authors.forename: Gina H
authors.initials: GH
authors.lastname: Lu
authors.forename: Andrew
authors.initials: A
authors.lastname: Robertson
authors.forename: Catherine
authors.initials: C
authors.lastname: Sekerke
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D032342:Muscle Cells / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin