title: Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.
abstract: The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.
authors.affiliation: Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA. jeffrey.a.pfefferkorn@pfizer.com
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Richard
authors.initials: R
authors.lastname: Hutchings
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Cheng
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Bruce
authors.initials: B
authors.lastname: Auerbach
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bush
authors.forename: Chitase
authors.initials: C
authors.lastname: Lee
authors.forename: Noe
authors.initials: N
authors.lastname: Erasga
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bowles
authors.forename: David C
authors.initials: DC
authors.lastname: Boyles
authors.forename: Gina
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authors.lastname: Lu
authors.forename: Catherine
authors.initials: C
authors.lastname: Sekerke
authors.forename: Valerie
authors.initials: V
authors.lastname: Askew
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.forename: Lisa
authors.initials: L
authors.lastname: Dillon
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Lin
authors.forename: Andrew
authors.initials: A
authors.lastname: Robertson
authors.forename: Karl
authors.initials: K
authors.lastname: Olsen
authors.forename: Carine
authors.initials: C
authors.lastname: Boustany
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: Theunis C
authors.initials: TC
authors.lastname: Goosen
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sahasrabudhe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chupka
authors.forename: David B
authors.initials: DB
authors.lastname: Duignan
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Renato
authors.initials: R
authors.lastname: Scialis
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Bi
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bakker-Arkema
authors.forename: Paul
authors.initials: P
authors.lastname: Barclay
authors.forename: Erick
authors.initials: E
authors.lastname: Kindt
authors.forename: Vu
authors.initials: V
authors.lastname: Le
authors.forename: Jaap W
authors.initials: JW
authors.lastname: Mandema
authors.forename: Mark
authors.initials: M
authors.lastname: Milad
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Tait
authors.forename: Robert
authors.initials: R
authors.lastname: Kennedy
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: Mark
authors.initials: M
authors.lastname: Kowala
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D022781:Hepatocytes / Q000187:drug effects; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects*; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014018:Tissue Distribution
chemical_list: C526799:7-(2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl)-3,5-dihydroxyheptanoic acid; C560211:7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D011720:Pyrazoles