ABSTRACT
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Animals , Binding, Competitive , Biological Availability , Cell Membrane Permeability , Crystallography, X-Ray , Drug Discovery , Humans , Isoenzymes , Models, Molecular , Molecular Docking Simulation , Phosphoinositide-3 Kinase Inhibitors/toxicity , Rats , Structure-Activity RelationshipABSTRACT
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
Subject(s)
Indazoles/chemistry , Receptors, Glucocorticoid/agonists , Sulfonamides/chemical synthesis , Binding Sites , Cell Line, Tumor , Computer Simulation , Drug Evaluation, Preclinical , Humans , Hydrophobic and Hydrophilic Interactions , Indazoles/chemical synthesis , Indazoles/pharmacology , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
A new synthesis of 1-substituted-1H-indazoles via 1,3-dipolar cycloaddition of nitrile imines to benzyne is described. The reaction is completed within 5 min, affording the corresponding N(1)-C(3) disubstituted indazoles in moderate to excellent yields.
Subject(s)
Benzene Derivatives/chemistry , Imines/chemistry , Indazoles/chemical synthesis , Nitriles/chemistry , Combinatorial Chemistry Techniques , Cyclization , Indazoles/chemistry , Molecular StructureABSTRACT
An efficient synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reaction partners mediated by TBAF. Reactions are complete within 30 s, giving the target products in good to excellent yield.
Subject(s)
Benzene Derivatives/chemistry , Isoxazoles/chemical synthesis , Nitriles/chemistry , Benzene Derivatives/chemical synthesis , Catalysis , Cyclization , Isoxazoles/chemistry , Nitriles/chemical synthesis , Oxides/chemical synthesis , Oxides/chemistryABSTRACT
An efficient protocol for the synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reactants simultaneously.
