ABSTRACT
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Subject(s)
Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Quinolines/pharmacology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Animals , B-Lymphocytes/drug effects , Crystallography, X-Ray , Hemocyanins/drug effects , Humans , Immunoglobulin G/drug effects , Immunoglobulin M/drug effects , Mice , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Class I Phosphatidylinositol 3-Kinases/metabolism , Humans , Male , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Subject(s)
Adenosine/pharmacology , Autoimmune Diseases/prevention & control , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Inflammation/prevention & control , Protein Kinase Inhibitors/pharmacology , Quinolines/pharmacology , Adenosine/chemistry , Adenosine/metabolism , Animals , Cells, Cultured , Class I Phosphatidylinositol 3-Kinases/chemistry , Class I Phosphatidylinositol 3-Kinases/metabolism , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Female , Humans , Mice, Inbred BALB C , Mice, Transgenic , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Quinolines/chemistry , Quinolines/metabolism , Rats, Inbred Lew , Sf9 Cells , Structure-Activity RelationshipABSTRACT
The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Alkynes/chemical synthesis , Alkynes/chemistry , Alkynes/pharmacology , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Drug Design , HT29 Cells , Humans , Hydrogen Bonding , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , NF-kappaB-Inducing KinaseABSTRACT
PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
Subject(s)
PPAR gamma/agonists , Quinolines/chemistry , Sulfonamides/chemistry , Administration, Oral , Animals , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Diabetes Mellitus, Experimental/drug therapy , Half-Life , Insulin Resistance , Male , Mice , PPAR gamma/metabolism , Protein Structure, Tertiary , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Zucker , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.
Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Models, MolecularSubject(s)
Autoimmune Diseases/enzymology , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Inflammation/enzymology , Phosphoinositide-3 Kinase Inhibitors , Animals , Autoimmune Diseases/drug therapy , B-Lymphocytes/enzymology , Class Ia Phosphatidylinositol 3-Kinase/chemistry , Class Ib Phosphatidylinositol 3-Kinase/chemistry , Humans , Inflammation/drug therapy , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Targeted Therapy , Neutrophils/enzymology , Protein Conformation , T-Lymphocytes/enzymologyABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Quinolines/chemistry , Semicarbazides/chemistry , Thiourea/analogs & derivatives , Animals , Dogs , Female , Hepatocytes/metabolism , High-Throughput Screening Assays , Humans , I-kappa B Kinase/metabolism , Macaca mulatta , Male , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Semicarbazides/chemical synthesis , Semicarbazides/pharmacokinetics , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacokineticsABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
