title: Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus.
abstract: A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: B D
authors.initials: BD
authors.lastname: Roth
authors.forename: C J
authors.initials: CJ
authors.lastname: Blankley
authors.forename: A W
authors.initials: AW
authors.lastname: Chucholowski
authors.forename: E
authors.initials: E
authors.lastname: Ferguson
authors.forename: M L
authors.initials: ML
authors.lastname: Hoefle
authors.forename: D F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
authors.forename: C S
authors.initials: CS
authors.lastname: Sekerke
authors.forename: D R
authors.initials: DR
authors.lastname: Sliskovic
authors.forename: C D
authors.initials: CD
authors.lastname: Stratton
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D011753:Pyrones; D011758:Pyrroles