Discovery of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides as small molecule inhibitors of PCSK9

Allyn T Londregan; Gary Aspnes; Chris Limberakis; Paula M Loria; Kim F McClure; Donna N Petersen; Brian Raymer; Roger B Ruggeri; Liuqing Wei; Jun Xiao; David W Piotrowski

doi:10.1016/j.bmcl.2018.10.029

Discovery of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides as small molecule inhibitors of PCSK9

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3685-3688. doi: 10.1016/j.bmcl.2018.10.029. Epub 2018 Oct 22.

Affiliations

¹ Pfizer Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, United States. Electronic address: allyn.t.londregan@pfizer.com.
² Pfizer Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, United States.

PMID: 30482620
DOI: 10.1016/j.bmcl.2018.10.029

Abstract

A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures.

Keywords: Medchem; PCSK9; Parallel synthesis; SAR; Urea.

MeSH terms

Amides / chemistry*
Amides / metabolism
Amides / pharmacology
Animals
Cell Membrane Permeability / drug effects
Crystallography, X-Ray
Dogs
Humans
Inhibitory Concentration 50
Madin Darby Canine Kidney Cells
Molecular Conformation
PCSK9 Inhibitors*
Piperidines / chemistry*
Proprotein Convertase 9 / metabolism
Protease Inhibitors / chemistry*
Protease Inhibitors / metabolism
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Amides
PCSK9 Inhibitors
Piperidines
Protease Inhibitors
PCSK9 protein, human
Proprotein Convertase 9