2. Academic Validation
  3. Small molecule inhibitors of PCSK9. SAR investigations of head and amine groups

Small molecule inhibitors of PCSK9. SAR investigations of head and amine groups

  • Bioorg Med Chem Lett. 2023 Aug 15:92:129394. doi: 10.1016/j.bmcl.2023.129394.
Gary E Aspnes 1,  Steven B Coffey 1,  Etzer Darout 1,  Anne-Marie Dechert-Schmitt 1,  Robert G Dullea 1,  Adam S Kamlet 1,  Chris Limberakis 1,  Allyn T Londregan 1,  Kim F McClure 1,  Elnaz Menhaji-Klotz 1,  David W Piotrowski 2,  Jana Polivkova 1,  Brian Raymer 1,  Roger B Ruggeri 1,  Christopher T Salatto 1,  Meihua Tu 1,  Liuqing Wei 1,  Jun Xiao 1
Affiliations

Affiliations

  • 1 Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
  • 2 Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. Electronic address: [email protected].
PMID: 37379958 DOI: 10.1016/j.bmcl.2023.129394
Abstract

Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1). This work resulted in compound 3 that showed an improved safety profile. We hypothesized that this improvement was related to diminished binding of 3 to non-translating ribosomes and an apparent improvement in transcript selectivity. Herein, we describe our efforts to further optimize this series of inhibitors through modulation of the heterocyclic head group and the amine fragment. Some of the effort was guided by an emerging cryo electron microscopy structure of the binding mode of 1 in the ribosome. These efforts led to the identification of 15 that was deemed suitable for evaluation in a humanized PCSK9 mouse model and a rat toxicology study. Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate.

Keywords

PCSK9; Ribosome.

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