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1.
Bioorg Med Chem Lett ; 30(4): 126930, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926786

RESUMO

Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-ß in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Quinase 3 da Glicogênio Sintase/metabolismo , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade
2.
Pharmacol Ther ; 177: 23-31, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28202364

RESUMO

Decades of preclinical and natural history studies have highlighted the potential of fatty acid synthase (FASN) as a bona fide drug target for oncology. This review will highlight the foundational concepts upon which this perspective is built. Published studies have shown that high levels of FASN in patient tumor tissues are present at later stages of disease and this overexpression predicts poor prognosis. Preclinical studies have shown that experimental overexpression of FASN in previously normal cells leads to changes that are critical for establishing a tumor phenotype. Once the tumor phenotype is established, FASN elicits several changes to the tumor cell and becomes intertwined with its survival. The product of FASN, palmitate, changes the biophysical nature of the tumor cell membrane; membrane microdomains enable the efficient assembly of signaling complexes required for continued tumor cell proliferation and survival. Membranes densely packed with phospholipids containing saturated fatty acids become resistant to the action of other chemotherapeutic agents. Inhibiting FASN leads to tumor cell death while sparing normal cells, which do not have the dependence of this enzyme for normal functions, and restores membrane architecture to more normal properties thereby resensitizing tumors to killing by chemotherapies. One compound has recently reached clinical studies in solid tumor patients and highlights the need for continued evaluation of the role of FASN in tumor cell biology. Significant advances have been made and much remains to be done to optimally apply this class of pharmacological agents for the treatment of specific cancers.


Assuntos
Ácido Graxo Sintases/metabolismo , Neoplasias/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Ácido Graxo Sintases/antagonistas & inibidores , Ácido Graxo Sintases/imunologia , Humanos , Lipogênese , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Oncogenes , Prognóstico
3.
ChemMedChem ; 12(20): 1687-1692, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-28881459

RESUMO

Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.


Assuntos
Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Tetraciclinas/síntese química , Tetraciclinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Relação Estrutura-Atividade
4.
J Med Chem ; 60(20): 8482-8514, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29016121

RESUMO

In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases da Glicogênio Sintase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Animais , Células CHO , Cromatografia Líquida de Alta Pressão , Cricetulus , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Humanos , Hipoglicemiantes/metabolismo , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Pirimidinas/química , Pirimidinas/metabolismo , Ratos , Relação Estrutura-Atividade
5.
Open Biol ; 6(9)2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27655731

RESUMO

As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252-14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of ß-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site.

6.
Diabetes ; 52(3): 588-95, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12606497

RESUMO

Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Insulina/farmacologia , Aminopiridinas/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Células CHO , Cricetinae , Diabetes Mellitus/tratamento farmacológico , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Feminino , Expressão Gênica , Glicogênio Sintase/metabolismo , Hepatócitos/metabolismo , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptor de Insulina/genética , Transfecção
7.
Curr Pharm Des ; 10(10): 1105-37, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15078145

RESUMO

Originally identified as a modulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now understood to play an important regulatory role in a variety of pathways including initiation of protein synthesis, cell proliferation, cell differentiation, apoptosis, and is essential for embryonic development as a component of the Wnt signaling cascade. GSK3 can be considered as a target for both metabolic and neurological disorders. GSK3's association with neuronal apoptosis and hyper-phosphorylation of tau make this kinase an attractive therapeutic target for neurodegenerative conditions such as head trauma, stroke and Alzheimer's disease. While noting GSK3's many associated functions, this review will focus on GSK3 as a central negative regulator in the insulin signaling pathway, its role in insulin resistance, and the utility of GSK3 inhibitors for intervention and control of metabolic diseases including type 2 diabetes. Recent crystal structures, including the active (phosphorylated Tyr-216) form of GSK3beta, provide a wealth of structural information and greater understanding of GSK3's unique regulation and substrate specificity. Many potent and selective small molecule inhibitors of GSK3 have now been identified, and used in vitro to modulate glycogen metabolism and gene transcription, increase glycogen synthase activity and enhance insulin-stimulated glucose transport. The pharmacology of potent and selective GSK3 inhibitors (CT 99021 and CT 20026) is described in a number of in vitro and in vivo models following acute or chronic exposure. The efficacy of clinical candidates in diabetic primates and the implications for clinical development are discussed. The profile of activity is consistent with a unique form of insulin sensitization which is well suited for indications such as metabolic syndrome X and type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipoglicemiantes , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Modelos Moleculares , Estrutura Molecular , Especificidade por Substrato
8.
Curr Opin Drug Discov Devel ; 7(4): 446-59, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15338954

RESUMO

Hepatitis C virus (HCV) is a disease that has a growing impact worldwide. A combination therapy comprising interferon-alpha (IFNalpha) and ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes some serious side effects. Promising alternative approaches toward the control of HCV infection, and the development of new antiviral agents, include the use of NS3/4A serine protease and NS5B polymerase inhibitors. Successful proof-of-concept clinical trials of the NS3/4A protease inhibitor BILN-2061 have confirmed the usefulness of a peptidomimetic product-based approach, providing impetus for the generation of improved molecules. Preclinical results from the development of HCV polymerase inhibitors, both nucleoside and non-nucleoside, are promising. This review provides an overview of recent progress in these areas, and discusses the potential of various approaches toward small molecule HCV antivirals.


Assuntos
Antivirais/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Peso Molecular , Animais , Antivirais/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/fisiopatologia , Humanos
9.
J Org Chem ; 61(23): 8016-8023, 1996 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11667784

RESUMO

Substrate analogues of phosphatidylinositol (1) were synthesized and evaluated as potential inhibitors of the bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus. The chiral analogues of the water-soluble phospholipid substrate 5 were designed to probe the effects of varying the inositol C-2 hydroxyl group, which is generally believed to serve as the nucleophile in the first step of the hydrolysis of phosphatidylinositols by PI-PLC. In the analogues 6-9, the C-2 hydroxyl group on the inositol ring of the phosphatidylinositol derivatives was rationally altered in several ways. Inversion of the stereochemistry at C-2 of the inositol ring led to the scyllo derivative 6. The inositol C-2 hydroxy group was replaced with inversion by a fluorine to produce the scyllo-fluoro inositol 7 and with a hydrogen atom to furnish the 2-deoxy compound 8. The C-2 hydroxyl group was O-methylated to prepare the methoxy derivative 9. The natural inositol configuration at C-2 was retained in the nonhydrolyzable phosphorodithioate analogue 10. The inhibition of PI-PLC by each of these analogues was then analyzed in a continuous assay using D-myo-inositol 1-(4-nitrophenyl phosphate) (25) as a chromogenic substrate. The kinetic parameters for each of these phosphatidylinositol derivatives were determined, and each was found to be a competitive inhibitor with K(i)'s as follows: 6, 0.2 mM; 10, 0.6 mM; 8, 2.6 mM; 9, 6.6 mM; and 7, 8.8 mM. This study further establishes that the hydrolysis of phosphatidylinositol analogues by bacterial PI-PLC requires not only the presence of a C-2 hydroxyl group on the inositol ring, but the stereochemistry at this position must also correspond to the natural myo-configuration. For future inhibitor design, it is perhaps noteworthy that the best inhibitors 6 and 10 each possess a hydroxyl group at the C-2 position. Several of the inhibitors identified in this study are now being used to obtain crystallographic information for an enzyme-inhibitor complex to gain further insights regarding the mechanism of hydrolysis of phosphatidylinositides by this PI-PLC.

10.
ACS Med Chem Lett ; 2(1): 34-8, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900252

RESUMO

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties. A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered. Within this series a compound, 17, was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.

11.
ACS Med Chem Lett ; 2(10): 774-9, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900266

RESUMO

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.

12.
Mol Cell ; 21(6): 749-60, 2006 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-16543145

RESUMO

We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by AKT, for its role in the regulation of apoptosis. Upon IL-3 withdrawal, protein levels of MCL-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and apoptosis. MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. A phosphorylation-site mutant (MCL-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from apoptosis compared to wild-type MCL-1. The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.


Assuntos
Apoptose , Quinase 3 da Glicogênio Sintase/fisiologia , Interleucina-3/farmacologia , Membranas Mitocondriais/fisiologia , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Citocromos c/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Permeabilidade , Fosfatidilinositol 3-Quinases/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Homologia de Sequência de Aminoácidos , Fatores de Tempo , Transfecção
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