ABSTRACT
The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.
Subject(s)
Benzothiepins/pharmacology , Drug Discovery , Mood Disorders/drug therapy , Receptors, Neuropeptide Y/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Benzothiepins/chemical synthesis , Benzothiepins/chemistry , Biological Availability , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Mice , Molecular Structure , Mood Disorders/metabolism , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/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
Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
Subject(s)
Gene Rearrangement , Polycystic Kidney, Autosomal Dominant/genetics , TRPP Cation Channels/genetics , Tumor Suppressor Proteins/genetics , DNA Mutational Analysis/methods , DNA Mutational Analysis/standards , Family Health , Female , Gene Deletion , Humans , Male , Mutation , Pedigree , Polycystic Kidney, Autosomal Dominant/diagnosis , Tuberous Sclerosis Complex 2 ProteinABSTRACT
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
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
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
[Reaction: see text]. A synthesis of the title compounds, which have found use as inhibitors of certain receptor tyrosine kinases, was achieved using a Pictet-Spengler cyclization as a key step.
Subject(s)
Azepines/chemistry , Azepines/chemical synthesis , Catalysis , Cyclization , Molecular StructureABSTRACT
Pyrimido-oxazepine based sub-micromolar inhibitors (2-4) for Aurora and FLT-3 were designed and synthesized. These preliminary results supported the potential use of pyrimido-oxazepines as a versatile template for developing specific kinase inhibitors.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oxazepines/pharmacology , Phosphotransferases/antagonists & inhibitors , Pyrimidines/pharmacology , Aurora Kinases , Humans , Kinetics , Models, Molecular , Oxazepines/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Structure-Activity Relationship , fms-Like Tyrosine Kinase 3/antagonists & inhibitorsABSTRACT
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Humans , Microtubules/drug effects , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Tubulin Modulators/chemical synthesis , Tumor Cells, CulturedABSTRACT
A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Phthalazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Inhibitory Concentration 50 , Phthalazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.
