학술논문
Small molecule inhibitors of PCSK9. SAR investigations of head and amine groups.
Document Type
Academic Journal
Author
Aspnes GE; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Coffey SB; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Darout E; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Dechert-Schmitt AM; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Dullea RG; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Kamlet AS; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Limberakis C; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Londregan AT; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; McClure KF; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Menhaji-Klotz E; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Piotrowski DW; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. Electronic address: david.w.piotrowski@comcast.net.; Polivkova J; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Raymer B; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Ruggeri RB; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Salatto CT; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Tu M; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Wei L; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.; Xiao J; Pfizer Medicine Design, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors were employees of Pfizer when this work was completed.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors were employees of Pfizer when this work was completed.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)