title: Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors.
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.
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden. Electronic address: Ina.Terstiege@astrazeneca.com.
authors.forename: Ina
authors.initials: I
authors.lastname: Terstiege
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Matthew
authors.initials: M
authors.lastname: Perry
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Tyrchan
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Tor
authors.initials: T
authors.lastname: Svensson
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Lindmark
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Öster
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011719:Pyrazines; D014230:Triazoles; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
keywords: Aminopyrazine; Inflammation; PI3Kδ inhibitor; Phosphoinositide 3-kinase