Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors

Ina Terstiege; Matthew Perry; Jens Petersen; Christian Tyrchan; Tor Svensson; Helena Lindmark; Linda Öster

doi:10.1016/j.bmcl.2016.11.004

Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors

Bioorg Med Chem Lett. 2017 Feb 1;27(3):679-687. doi: 10.1016/j.bmcl.2016.11.004. Epub 2016 Nov 2.

Authors

Ina Terstiege¹, Matthew Perry², Jens Petersen³, Christian Tyrchan², Tor Svensson², Helena Lindmark³, Linda Öster³

Affiliations

¹ Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden. Electronic address: Ina.Terstiege@astrazeneca.com.
² Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
³ Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.

PMID: 28017532
DOI: 10.1016/j.bmcl.2016.11.004

Abstract

A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC₅₀⩽1nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20-120nM.

Keywords: Aminopyrazine; Inflammation; PI3Kδ inhibitor; Phosphoinositide 3-kinase.

MeSH terms

Animals
Binding Sites
Cell Line
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Crystallography, X-Ray
Enzyme Activation / drug effects
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Half-Life
Humans
Inhibitory Concentration 50
Molecular Dynamics Simulation
Protein Binding
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Protein Structure, Tertiary
Pyrazines / chemistry*
Pyrazines / metabolism
Pyrazines / pharmacology*
Rats
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology

Substances

Enzyme Inhibitors
Protein Isoforms
Pyrazines
Triazoles
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human