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.
Ina Terstiege  1 ,  Matthew Perry  2 ,  Jens Petersen  3 ,  Christian Tyrchan  2 ,  Tor Svensson  2 ,  Helena Lindmark  3 ,  Linda Öster  3
Affiliations
  • 1. Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden. Electronic address: [email protected].
  • 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.
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