ABSTRACT
Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.
Subject(s)
Asthma/drug therapy , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Class I Phosphatidylinositol 3-Kinases/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein ConformationABSTRACT
The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.
ABSTRACT
A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Binding Sites , Cell Degranulation/drug effects , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Mast Cells/enzymology , Mast Cells/physiology , Molecular Docking Simulation , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Syk KinaseABSTRACT
The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.
