title: Discovery of pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase.
abstract: In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bratton
authors.forename: Bruce
authors.initials: B
authors.lastname: Auerbach
authors.forename: Chulho
authors.initials: C
authors.lastname: Choi
authors.forename: Lisa
authors.initials: L
authors.lastname: Dillon
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Gina
authors.initials: G
authors.lastname: Lu
authors.forename: Karl
authors.initials: K
authors.lastname: Olsen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Andrew
authors.initials: A
authors.lastname: Robertson
authors.forename: Catherine
authors.initials: C
authors.lastname: Sekerke
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: Paul C
authors.initials: PC
authors.lastname: Unangst
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D011758:Pyrroles; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases