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Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents.
Londregan, Allyn T; Wei, Liuqing; Xiao, Jun; Lintner, Nathanael G; Petersen, Donna; Dullea, Robert G; McClure, Kim F; Bolt, Michael W; Warmus, Joseph S; Coffey, Steven B; Limberakis, Chris; Genovino, Julien; Thuma, Benjamin A; Hesp, Kevin D; Aspnes, Gary E; Reidich, Benjamin; Salatto, Christopher T; Chabot, Jeffrey R; Cate, Jamie H D; Liras, Spiros; Piotrowski, David W.
Affiliation
  • Londregan AT; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Wei L; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Xiao J; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Lintner NG; Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , California 94720 , United States.
  • Petersen D; Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism , Pfizer Worldwide Research and Development , Groton , Connecticut 06340 , United States.
  • Dullea RG; Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • McClure KF; Pfizer Medicinal Chemistry, Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • Bolt MW; Drug Safety Research & Development , Pfizer Worldwide Research & Development , Cambridge , Massachusetts 02139 , United States.
  • Warmus JS; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Coffey SB; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Limberakis C; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Genovino J; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Thuma BA; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Hesp KD; Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • Aspnes GE; Pfizer Medicinal Chemistry, Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • Reidich B; Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • Salatto CT; Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • Chabot JR; Pfizer Pharmacokinetics, Dynamics and Metabolism Modeling and Simulation , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • Cate JHD; Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , California 94720 , United States.
  • Liras S; QB3 Institute , University of California, Berkeley , Berkeley , California 94720 , United States.
  • Piotrowski DW; Department of Chemistry , University of California, Berkeley , Berkeley , California 94720 , United States.
J Med Chem ; 61(13): 5704-5718, 2018 07 12.
Article in En | MEDLINE | ID: mdl-29878763
ABSTRACT
The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.
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Full text: 1 Database: MEDLINE Main subject: Protease Inhibitors / PCSK9 Inhibitors Limits: Animals Language: En Year: 2018 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Protease Inhibitors / PCSK9 Inhibitors Limits: Animals Language: En Year: 2018 Type: Article