2. Academic Validation
  3. Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

  • J Med Chem. 2018 Jul 12;61(13):5704-5718. doi: 10.1021/acs.jmedchem.8b00650.
Allyn T Londregan 1,  Liuqing Wei 1,  Jun Xiao 1,  Nathanael G Lintner 2,  Donna Petersen 3,  Robert G Dullea 4,  Kim F McClure 5,  Michael W Bolt 6,  Joseph S Warmus 1,  Steven B Coffey 1,  Chris Limberakis 1,  Julien Genovino 1,  Benjamin A Thuma 1,  Kevin D Hesp 1,  Gary E Aspnes 5,  Benjamin Reidich 4,  Christopher T Salatto 4,  Jeffrey R Chabot 7,  Jamie H D Cate 2 8 9 10,  Spiros Liras 5,  David W Piotrowski 1
Affiliations

Affiliations

  • 1 Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
  • 2 Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , California 94720 , United States.
  • 3 Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism , Pfizer Worldwide Research and Development , Groton , Connecticut 06340 , United States.
  • 4 Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • 5 Pfizer Medicinal Chemistry, Internal Medicine Research Unit , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • 6 Drug Safety Research & Development , Pfizer Worldwide Research & Development , Cambridge , Massachusetts 02139 , United States.
  • 7 Pfizer Pharmacokinetics, Dynamics and Metabolism Modeling and Simulation , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , United States.
  • 8 QB3 Institute , University of California, Berkeley , Berkeley , California 94720 , United States.
  • 9 Department of Chemistry , University of California, Berkeley , Berkeley , California 94720 , United States.
  • 10 Physical Biosciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.
PMID: 29878763 DOI: 10.1021/acs.jmedchem.8b00650
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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