ABSTRACT
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Adenosine Triphosphate/metabolism , Administration, Oral , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/administration & dosage , Humans , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Mice, Inbred C57BL , Multiple Sclerosis/drug therapy , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phthalimides/chemistry , Structure-Activity RelationshipABSTRACT
A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.
Subject(s)
Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Cell Line , Enzyme Inhibitors/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/metabolism , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Piperidines/metabolism , Protein Conformation , Substrate SpecificityABSTRACT
The solution-phase synthesis of amido-, urea-, and aminofuranoses was achieved. Alkylated furanose aldehydes were treated with primary amines in the presence of sodium triacetoxyborohydride to give secondary amines. Subsequent acylation with acid chlorides and isocyanates afforded amidofuranoses and ureafuranoses, respectively. Second, reductive amination of furanose aldehydes with secondary amines yielded tertiary amines. The resulting acetonides were treated with alcohols in the presence of acid to yield mixed acetals. In the library syntheses, functionalized scavenger resins were used in the purification of intermediates and products.
