ABSTRACT
New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).
Subject(s)
Acetates/chemical synthesis , Alkynes/chemical synthesis , Anti-Allergic Agents/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfones/chemical synthesis , Acetates/pharmacokinetics , Acetates/pharmacology , Administration, Oral , Alkynes/pharmacokinetics , Alkynes/pharmacology , Animals , Anti-Allergic Agents/pharmacokinetics , Anti-Allergic Agents/pharmacology , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Binding, Competitive , Blood Proteins/metabolism , Caco-2 Cells , Cell Membrane Permeability , Cell Shape , Chemotaxis, Leukocyte , Dermatitis, Contact/drug therapy , Eosinophils/drug effects , Eosinophils/pathology , Eosinophils/physiology , Female , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Ovalbumin/immunology , Phenoxyacetates , Protein Binding , Pulmonary Eosinophilia/drug therapy , Pulmonary Eosinophilia/immunology , Radioligand Assay , Rats , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Subject(s)
Antineoplastic Agents/chemistry , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Drug Discovery , Fingolimod Hydrochloride , High-Throughput Screening Assays , Humans , Mice , Microsomes, Liver/metabolism , Propylene Glycols/chemistry , Propylene Glycols/pharmacology , Rats , Receptors, Lysosphingolipid/metabolism , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity RelationshipABSTRACT
Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethylene thiazolidinediones as selective, ATP-competitive PI3Kgamma inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kgamma identified key pharmacophore features for potency and selectivity. An acidic NH group on the thiazolidinedione moiety and a hydroxy group on the furan-2-yl-phenyl part of the molecule play crucial roles in binding to PI3K and contribute to class IB PI3K selectivity. Compound 26 (AS-252424), a potent and selective small-molecule PI3Kgamma inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects. Oral administration of 26 in a mouse model of acute peritonitis led to a significant reduction of leukocyte recruitment.
