ABSTRACT
Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.
Subject(s)
Autoimmune Diseases/drug therapy , Indoles/chemistry , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Animals , Humans , Mice , Models, Molecular , Structure-Activity RelationshipABSTRACT
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
Subject(s)
Antirheumatic Agents/chemistry , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/therapeutic use , Pyrroles/chemistry , Pyrroles/therapeutic use , Agammaglobulinaemia Tyrosine Kinase , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/enzymology , Humans , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Subject(s)
Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazines/chemistry , Animals , Aurora Kinase A , Aurora Kinases , Drug Evaluation, Preclinical , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , RatsABSTRACT
A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemistry , Pyridines/chemistry , Amino Acid Substitution , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemistry , Amino Acid Substitution , Binding Sites , Computer Simulation , Drug Evaluation, Preclinical , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.
Subject(s)
Inflammatory Bowel Diseases/drug therapy , Isoindoles/chemistry , Receptors, CCR/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Chemistry Techniques, Synthetic , Chemotaxis/drug effects , Colitis/chemically induced , Colitis/drug therapy , Disease Models, Animal , Humans , Isoindoles/administration & dosage , Isoindoles/pharmacokinetics , Male , Mice, Inbred C57BL , Receptors, CCR/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzazepines/chemical synthesis , Cell Cycle Proteins/antagonists & inhibitors , Lactams/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiones/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Mice , Mice, Nude , Mitosis , Models, Molecular , Neoplasm Transplantation , Protein Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiones/pharmacokinetics , Thiones/pharmacology , Transplantation, Heterologous , Polo-Like Kinase 1ABSTRACT
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Crystallography, X-Ray , Drug Design , Melanoma, Experimental/drug therapy , Melanoma, Experimental/enzymology , Melanoma, Experimental/pathology , Mice , Mice, Nude , Models, Molecular , Mutation , Proto-Oncogene Proteins B-raf/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Recently, significant attention has been focused on the synthesis small-molecule libraries based on natural product or natural product-like structures. In this paper, we report our initial studies on the use of the 1,7-dioxaspiro[5,5]undecane (spiroketal) moiety as a rigid-core template for elaboration using parallel synthesis techniques. The synthesis of a spiroketal scaffold that is reminiscent of the spiroketal subunits found in the spiroketal macrolide antibiotics will be described. Elaboration of three independently addressable functional groups on the scaffold using solution-phase parallel synthesis techniques led to the preparation of a small library of natural product-like compounds. These studies pave the way for evaluation of highly functionalized spiroketals in phenotypic assays and as prospective antagonists of protein-protein interactions.