title: Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design.
abstract: An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.
authors.affiliation: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. sdlarsen@umich.edu
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Toni-Jo
authors.initials: TJ
authors.lastname: Poel
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Sorenson
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Tait
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: 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
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Auerbach
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D006903:Hydroxymethylglutaryl CoA Reductases