ABSTRACT
In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.
ABSTRACT
Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
Subject(s)
Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Binding Sites/drug effects , Humans , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
Subject(s)
Thiazoles/chemical synthesis , Thiazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Caco-2 Cells , Combinatorial Chemistry Techniques , Drug Design , Humans , Indoles/pharmacology , Molecular Structure , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Oligonucleotides , Phthalazines/pharmacology , Pyridines/pharmacology , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Subject(s)
Phthalazines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Female , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred Strains , Phthalazines/administration & dosage , Phthalazines/chemical synthesis , Piperidines , Quinazolines , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitorsABSTRACT
We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.
Subject(s)
Ketones , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Combinatorial Chemistry Techniques , Inhibitory Concentration 50 , Ketones/chemical synthesis , Ketones/chemistry , Ketones/pharmacology , Mice , Molecular Structure , Piperidines/pharmacology , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
Novel derivatives of 1,2,4-triazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds display VEGFR-2 inhibitory activity comparable to that of Vatalanib and Vandetanib in both homogenous time-resolved fluorescence enzymatic and cellular assays. Several active molecules feature high intrinsic permeability (>30 x 10(-5) cm/min) across Caco-2 cell monolayer.
Subject(s)
Aniline Compounds/chemistry , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Triazoles/pharmacology , Cells, Cultured , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Triazoles/chemistryABSTRACT
We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases VEGFR-2 and -1. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib(trade)) and ZD6474 (Vandetanib(trade mark)). High permeability of active compounds across the Caco-2 cell monolayer (>40 x 10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Subject(s)
Amides/chemistry , Azoles/chemistry , Chemistry, Pharmaceutical/methods , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Adenosine Triphosphate/chemistry , Azoles/pharmacology , Binding, Competitive , Caco-2 Cells , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Models, Chemical , Phthalazines/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Pyridines/pharmacology , Quinazolines/pharmacologyABSTRACT
We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Subject(s)
Azoles/chemical synthesis , Azoles/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Azoles/pharmacokinetics , Binding, Competitive , Caco-2 Cells , Cell Membrane Permeability , Humans , Inhibitory Concentration 50 , Intestinal Absorption , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Novel potent derivatives of phthalazine are described as an adenosine triphosphate-competitive inhibitors of vascular endothelial growth factor receptors I and II. A number of compounds display vascular endothelial growth factor receptor II inhibitory activity reaching that of Vatalanib A (IC(50): < 50 nm) in an homogenous time-resolved fluorescence enzymatic assay.
Subject(s)
Phthalazines/chemistry , Phthalazines/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Binding Sites , Binding, Competitive , Humans , Inhibitory Concentration 50 , Phthalazines/chemical synthesis , Protein Binding , Structure-Activity RelationshipABSTRACT
Novel potent derivatives of phthalazine are described as ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds display VEGFR-2 inhibitory activity reaching that of Vatalanib 3 (IC50 < 100 nm) in an HTRF enzymatic assay. Several derivatives also show good potential for the development as VEGFR-2 specific inhibitors showing 15-20-fold selectivity over VEGFR-1.
Subject(s)
Phthalazines/chemistry , Phthalazines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Binding, Competitive , Drug Design , Humans , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Subject(s)
Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Antineoplastic Agents/pharmacology , Azepines/chemistry , Cell Line, Tumor , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitory Concentration 50 , Neoplasm Proteins/antagonists & inhibitors , Phosphorylation/drug effects , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
Subject(s)
Receptors, G-Protein-Coupled/agonists , Animals , Binding, Competitive , COS Cells , Calcium/metabolism , Cell Movement , Chlorocebus aethiops , Databases as Topic , Dose-Response Relationship, Drug , Enzyme Activation , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Humans , Ligands , Microscopy, Fluorescence , Models, Biological , Models, Molecular , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Conformation , Receptors, Estrogen/metabolism , Signal Transduction , Time FactorsABSTRACT
We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Subject(s)
Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Caco-2 Cells , Humans , Models, MolecularABSTRACT
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Subject(s)
Isoquinolines/pharmacology , Phthalazines/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Fluoroimmunoassay , Humans , Inhibitory Concentration 50 , Isoquinolines/chemical synthesis , Phthalazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Azepines/chemistry , Binding Sites , Cell Proliferation/drug effects , Cells, Cultured , Humans , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Subject(s)
Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Animals , Antimitotic Agents/chemistry , Antimitotic Agents/classification , Biopolymers/chemistry , Biopolymers/metabolism , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Protein Conformation/drug effects , Structure-Activity RelationshipABSTRACT
A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice.
Subject(s)
Benzamides/pharmacology , Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , In Vitro Techniques , Mice , Models, Animal , Molecular Sequence Data , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model.
Subject(s)
Carbanilides/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Lung Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Animals , Carbanilides/chemical synthesis , Carbanilides/classification , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/classification , In Vitro Techniques , Melanoma, Experimental/secondary , Mice , Molecular Structure , Molecular Weight , Neoplasm Metastasis/drug therapy , Structure-Activity RelationshipABSTRACT
Novel potent derivatives of N-(aryl)-4-(azolylethyl)thiazole-5-carboxamides are described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido pharmacophore, both dual and specific VEGFR-2 thiazoles were identified.
Subject(s)
Enzyme Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amides/chemistry , Animals , CHO Cells , Cricetinae , Inhibitory Concentration 50 , Molecular Structure , Thiazoles/chemistryABSTRACT
A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.