RESUMO
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/enzimologia , Regulação Alostérica , Inibidores de Integrase de HIV/química , Estrutura MolecularRESUMO
2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity.
Assuntos
2',5'-Oligoadenilato Sintetase/imunologia , Antivirais/farmacologia , Endorribonucleases/imunologia , Exorribonucleases/química , Imunidade Inata , Bibliotecas de Moléculas Pequenas/farmacologia , 2',5'-Oligoadenilato Sintetase/genética , Nucleotídeos de Adenina/imunologia , Nucleotídeos de Adenina/metabolismo , Antivirais/síntese química , Cristalografia por Raios X , Vírus da Encefalomiocardite/genética , Vírus da Encefalomiocardite/metabolismo , Endorribonucleases/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Exorribonucleases/antagonistas & inibidores , Exorribonucleases/genética , Exorribonucleases/imunologia , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HeLa , Humanos , Interferon-alfa/farmacologia , Modelos Moleculares , Oligorribonucleotídeos/imunologia , Oligorribonucleotídeos/metabolismo , Poli I-C/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vírus Sinciciais Respiratórios/genética , Vírus Sinciciais Respiratórios/metabolismo , Rhinovirus/genética , Rhinovirus/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-AtividadeRESUMO
HIV-1 replication in the presence of antiviral agents results in evolution of drug-resistant variants, motivating the search for additional drug classes. Here we report studies of GSK1264, which was identified as a compound that disrupts the interaction between HIV-1 integrase (IN) and the cellular factor lens epithelium-derived growth factor (LEDGF)/p75. GSK1264 displayed potent antiviral activity and was found to bind at the site occupied by LEDGF/p75 on IN by x-ray crystallography. Assays of HIV replication in the presence of GSK1264 showed only modest inhibition of the early infection steps and little effect on integration targeting, which is guided by the LEDGF/p75-IN interaction. In contrast, inhibition of late replication steps was more potent. Particle production was normal, but particles showed reduced infectivity. GSK1264 promoted aggregation of IN and preformed LEDGF/p75-IN complexes, suggesting a mechanism of inhibition. LEDGF/p75 was not displaced from IN during aggregation, indicating trapping of LEDGF/p75 in aggregates. Aggregation assays with truncated IN variants revealed that a construct with catalytic and C-terminal domains of IN only formed an open polymer associated with efficient drug-induced aggregation. These data suggest that the allosteric inhibitors of IN are promising antiviral agents and provide new information on their mechanism of action.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Integrase de HIV/metabolismo , HIV-1/fisiologia , Multimerização Proteica , Fatores de Transcrição/metabolismo , Replicação Viral/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/genética , Linhagem Celular , Cristalografia por Raios X , Integrase de HIV/química , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Humanos , Estrutura Terciária de Proteína , Fatores de Transcrição/química , Fatores de Transcrição/genética , Replicação Viral/fisiologiaRESUMO
Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Ratos , Animais , Cães , Capsídeo , Proteínas do Capsídeo , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológicoRESUMO
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/síntese química , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Glicemia/análise , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/farmacologia , ortoaminobenzoatos/sangue , ortoaminobenzoatos/químicaRESUMO
Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Fosforilase/antagonistas & inibidores , Imidas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/química , Cristalografia por Raios X , Citocromo P-450 CYP2C9 , Cães , Desenho de Fármacos , Glicina/química , Glicogênio Fosforilase/metabolismo , Humanos , Imidas/química , Concentração Inibidora 50 , Fígado/enzimologia , Conformação Molecular , Ratos , ortoaminobenzoatos/químicaRESUMO
Furin, also called proprotein convertase subtilisin/kexin 3 (PCSK3), is a calcium-dependent serine endoprotease that processes a wide variety of proproteins involved in cell function and homeostasis. Dysregulation of furin has been implicated in numerous disease states, including cancer and fibrosis. Mammalian cell expression of the furin ectodomain typically produces a highly glycosylated, heterogeneous protein, which can make crystallographic studies difficult. Here, the expression and purification of nonglycosylated human furin using the BacMam technology and site-directed mutagenesis of the glycosylation sites is reported. Nonglycosylated furin produced using this system retains full proteolytic activity indistinguishable from that of the glycosylated protein. Importantly, the nonglycosylated furin protein reliably forms extremely durable apo crystals that diffract to high resolution. These crystals can be soaked with a wide variety of inhibitors to enable a structure-guided drug-discovery campaign.
Assuntos
Apoproteínas/química , Bioquímica/métodos , Furina/química , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Glicosilação , Células HEK293 , Humanos , Domínios Proteicos , Estrutura Secundária de ProteínaRESUMO
A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.
Assuntos
Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Sítio Alostérico , Cristalografia por Raios X , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Naftiridinas/química , Naftiridinas/uso terapêutico , Replicação Viral/efeitos dos fármacosRESUMO
We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.
Assuntos
Benzimidazóis/síntese química , Modelos Moleculares , Receptor TIE-2/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Camundongos , Estrutura Molecular , Células NIH 3T3 , Fosforilação , Receptor TIE-2/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank (PDB) archive, â¼75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic Data Center/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the PDB? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated.
Assuntos
Bases de Dados de Proteínas , Proteínas/química , Cristalografia por Raios X , Curadoria de Dados , Guias como Assunto , Ligantes , Modelos Moleculares , Conformação ProteicaRESUMO
Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger 3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase 4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an attractive target for the treatment of asthma and COPD. We have determined crystal structures of the catalytic domain of PDE4B complexed with AMP (2.0 A), 8-Br-AMP (2.13 A) and the potent inhibitor rolipram (2.0 A). All the ligands bind in the same hydrophobic pocket and can interact directly with the active site metal ions. The identity of these metal ions was examined using X-ray anomalous difference data. The structure of the AMP complex confirms the location of the catalytic site and allowed us to speculate about the detailed mechanism of catalysis. The high-resolution structures provided the experimental insight into the nucleotide selectivity of phosphodiesterase. 8-Br-AMP binds in the syn conformation to the enzyme and demonstrates an alternative nucleotide-binding mode. Rolipram occupies much of the AMP-binding site and forms two hydrogen bonds with Gln443 similar to the nucleotides.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/química , Trifosfato de Adenosina/análogos & derivados , 3',5'-AMP Cíclico Fosfodiesterases/genética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Monofosfato de Adenosina/química , Trifosfato de Adenosina/química , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Humanos , Técnicas In Vitro , Substâncias Macromoleculares , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Inibidores de Fosfodiesterase/química , Estrutura Terciária de Proteína , Rolipram/química , Homologia de Sequência de Aminoácidos , Eletricidade EstáticaRESUMO
A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.
Assuntos
Inibidores da Angiogênese/síntese química , Compostos de Anilina/síntese química , Oxazóis/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Cães , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Oxazóis/farmacocinética , Oxazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Veias Umbilicais/citologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir's antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir's prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.
Assuntos
Inibidores de Integrase de HIV/metabolismo , Integrase de HIV/genética , HIV-1/genética , HIV-1/metabolismo , Compostos Heterocíclicos com 3 Anéis/metabolismo , Provírus/genética , Farmacorresistência Viral/genética , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Repetição Terminal Longa de HIV/genética , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Cinética , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação de Ácido Nucleico , Oxazinas , Piperazinas , Ligação Proteica , Conformação Proteica , PiridonasRESUMO
Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.
RESUMO
A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
Assuntos
Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/química , Cristalografia por Raios X , HIV-1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
Repression of gene transcription by the nuclear receptor Rev-erbalpha plays an integral role in the core molecular circadian clock. We report the crystal structure of a nuclear receptor-co-repressor (N-CoR) interaction domain 1 (ID1) peptide bound to truncated human Rev-erbalpha ligand-binding domain (LBD). The ID1 peptide forms an unprecedented antiparallel beta-sheet with Rev-erbalpha, as well as an alpha-helix similar to that seen in nuclear receptor ID2 crystal structures but out of register by four residues. Comparison with the structure of Rev-erbbeta bound to heme indicates that ID1 peptide and heme induce substantially different conformational changes in the LBD. Although heme is involved in Rev-erb repression, the structure suggests that Rev-erbalpha could also mediate repression via ID1 binding in the absence of heme. The previously uncharacterized secondary structure induced by ID1 peptide binding advances our understanding of nuclear receptor-co-repressor interactions.
Assuntos
Correpressor 1 de Receptor Nuclear/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/química , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Correpressor 1 de Receptor Nuclear/química , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Alinhamento de SequênciaRESUMO
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Indazóis , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.
Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor TIE-2/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Área Sob a Curva , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HT29 , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Modelos Moleculares , Transplante de Neoplasias , RNA/biossíntese , RNA/genéticaRESUMO
PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.