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1.
Eur J Med Chem ; 181: 111576, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400709

RESUMO

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.


Assuntos
Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Click , Citocinas/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Triazóis/farmacocinética
2.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
3.
Cancer Sci ; 110(10): 3306-3314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361380

RESUMO

Isocitrate dehydrogenase 2 (IDH2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG-221, an inhibitor primarily targeting the IDH2-R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG-221 has weak inhibitory activity toward IDH2-R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2-R140Q and IDH2-R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)-2-hydroxyglutarate (2-HG) production and induced differentiation in cells expressing IDH2-R140Q and IDH2-R172K, but not in cells expressing wild-type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2-R140Q and IDH2-R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2-R140Q, but not with IDH2-R172K. TQ05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2-HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.


Assuntos
Substituição de Aminoácidos , Inibidores Enzimáticos/administração & dosagem , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Neoplasias/tratamento farmacológico , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Células HEK293 , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/química , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Top Curr Chem (Cham) ; 377(4): 19, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165274

RESUMO

This review is an effort to summarize recent developments in synthesis of O-glycosides and N-, C-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O-glycosides used in the treatment of diabetes are presented, followed by the N-glycosides and finally the C-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C-Glycosyl compounds mimicking O-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C-glycosides. Also N-glycosides such as N-(ß-D-glucopyranosyl)-amides, N-(ß-D-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5. In Sect. 6, biological mechanisms of action of the glycosides and patents of marketed drugs are described.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas/métodos , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Relação Estrutura-Atividade
5.
Molecules ; 24(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195673

RESUMO

Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3-0.5 µM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (∼36% of hepatic blood flow), acceptable half-life (∼4.6 h), and high oral bioavailability (∼96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Injeções Intravenosas , Masculino , Camundongos Endogâmicos ICR , Modelos Moleculares , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Expert Opin Pharmacother ; 20(14): 1711-1718, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31169040

RESUMO

Introduction: Influenza represents a major public health threat worldwide. Implementation of good personal health and hygiene habits, together with vaccination, is the most effective tools to reduce influenza burden both in community and in healthcare setting. However, achieving adequate vaccination rates is challenging, and vaccination does not always guarantee complete protection. Neuraminidase inhibitors represent an important measure to reduce the risk of influenza-related complications among high-risk patients developing influenza infection. Areas covered: Neuraminidase inhibitors have been proven to be safe and effective in reducing influenza severity, duration of symptoms, hospitalizations, and influenza-related-mortality. Here the authors review the available data on neuraminidase inhibitors, including the mechanism of action, pharmacokinetics, efficacy, safety and current indications for their use in clinical practice. Expert opinion: Although vaccination is the most effective tool to reduce influenza-associated morbidity and mortality, neuraminidase inhibitors represent an important option for the treatment of patients with influenza infection, particularly in high-risk categories. Moreover, antivirals play an important role in influenza prevention and prophylaxis in selected settings.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Antivirais/farmacocinética , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Oseltamivir/farmacocinética , Oseltamivir/uso terapêutico , Zanamivir/farmacocinética , Zanamivir/uso terapêutico
7.
Eur J Med Chem ; 178: 93-107, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176098

RESUMO

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17ß-HSD1 and 17ß-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17ß-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17ß-HSD1 and 17ß-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17ß-HSD1 and 17ß-HSD2.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Estradiol Desidrogenases/antagonistas & inibidores , Fenóis/farmacocinética , Tiofenos/farmacocinética , Animais , Sítios de Ligação , Desenho de Drogas , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Estradiol Desidrogenases/química , Estradiol Desidrogenases/metabolismo , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-30901732

RESUMO

As a novel non-purine xanthine oxidase inhibitor, WSJ-557 is a potential drug for gout. To determine the WSJ-557 concentration in plasma and various tissues of rats, a fast and sensitive method was first established by the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in this paper. The liquid-liquid extraction of ethyl acetate was adopted for the sample preparation, and carbamazepine was taken as the internal standard. In the process of chromatographic separation, MRM transitions for WSJ-557 and carbamazepine (internal standard, IS) were m/z 316.1 → 260.0 and m/z 237.0 → 194.0, correspondingly. The great linearity of WSJ-557 in all bio-samples was found in the corresponding concentration range (r > 0.99). The intra- and inter-day precision (RSD%) were below 9.5% in various tissues and plasma, whose accuracy (RE%) was within ±9.2%. This method was resoundingly employed to the WSJ-557 study on rat pharmacokinetics and tissue distribution after the intravenous administration and oral administration. The average absolute bioavailability (F) of WSJ-557 was 6.48%. The highest distribution level of gastric and intestinal tissues indicated that WSJ-557 was first absorbed in the stomach and intestine. Moreover, this analytical method provides a significant approach for the further development and investigation of WSJ-557.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Xantina Oxidase/antagonistas & inibidores , Animais , Disponibilidade Biológica , Estabilidade de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Feminino , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Distribuição Tecidual
9.
Eur J Med Chem ; 170: 276-289, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30921693

RESUMO

Neutral sphingomyelinase 2 (nSMase2), a key enzyme in ceramide biosynthesis, is a new therapeutic target for the treatment of neurological disorders and cancer. Using 2,6-dimethoxy-4-[4-phenyl-5-(2-thienyl)-1H-imidazol-2-yl]phenol (DPTIP), our initial hit compound (IC50 = 30 nM) from nSMase2 screening efforts, as a molecular template, a series of 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol derivatives were designed, synthesized, and evaluated. Systematic examination of various regions of DPTIP identified the key pharmacophore required for potent nSMase2 inhibition as well as a number of compounds with the 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol scaffold with similar or higher inhibitory potency against nSMase2 as compared to DPTIP. Among them, 4-(4,5-diisopropyl-1H-imidazol-2-yl)-2,6-dimethoxyphenol (25b) was found to be metabolically stable against P450 metabolism in liver microsomes and displayed higher plasma exposure following oral administration as compared to DPTIP. Analysis of plasma samples identified an O-glucuronide as the major metabolite. Blockade of the phase II metabolism should further facilitate our efforts to identify potent nSMase2 inhibitors with desirable ADME properties.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Fenóis/química , Fenóis/farmacologia , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Animais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Imidazóis/metabolismo , Imidazóis/farmacocinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Fenóis/metabolismo , Fenóis/farmacocinética , Esfingomielina Fosfodiesterase/metabolismo
10.
Eur J Med Chem ; 166: 178-185, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711829

RESUMO

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC50 value of 0.190 µM, and showed remarkable selectivity over other protein tyrosine phosphatases (PTPs, 20-200 folds). In the SPR study, increasing concentrations of compound 22 led to concentration-dependent increases in binding responses, indicating that compound 22 could bind to the surface of PTP1B via noncovalent means. By treating insulin-resistant C2C12 myotubes with compound 22, enhanced insulin and leptin signaling pathways were observed. Long-term oral administration of compound 22 reduced the blood glucose level of diabetic BKS db mice. The glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) in BKS db mice showed that oral administration of compound 22 could increase insulin sensitivity. In addition, long-term oral administration of compound 22 could protect mice from obesity, which was not the result of toxicity. Our pharmacokinetics results from the rat-based assays showed that orally administered compound 22 was absorbed rapidly from the gastrointestinal tract, extensively distributed to the tissues, and rapidly eliminated from the body. All these results indicate that compound 22 could serve as a qualified agent to treat type II diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Obesidade/complicações , Fenóis/química , Fenóis/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Insulina/metabolismo , Resistência à Insulina , Leptina/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Fenóis/farmacocinética , Fenóis/uso terapêutico , Fosforilação/efeitos dos fármacos , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Segurança , Transdução de Sinais/efeitos dos fármacos
11.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1110-1111: 116-123, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802754

RESUMO

BLU-554 is a potent, highly selective oral FGFR4 inhibitor. A bioanalytical assay for quantification of BLU-554 in mouse plasma and six tissue homogenates (brain, kidney, liver, lung, small intestine, and spleen) was developed and validated using liquid chromatography with tandem mass spectrometric detection and with erlotinib as internal standard. After protein precipitation with acetonitrile in a 96-well format and separation on an XBridge® Peptide BEH C18 column by gradient elution using 0.2% (v/v) ammonium hydroxide (in water) and methanol, analytes were ionized by positive electrospray and monitored in the selected reaction monitoring mode by triple quadrupole mass spectrometry. The assay was validated in a 1-1000 ng/ml concentration range using calibration in mouse plasma. Precisions (intra-day and inter-day) were in the range 2.8-10.1% and accuracies were in between 88.5 and 96.6% for all levels in all matrices. The assay was successfully applied for a pilot pharmacokinetic and tissue distribution study in wild-type mice.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos/sangue , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Análise dos Mínimos Quadrados , Limite de Detecção , Masculino , Camundongos , Reprodutibilidade dos Testes
12.
Rev. esp. quimioter ; 32(1): 1-5, feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-182741

RESUMO

Baloxavir marboxil (ácido 5-hidroxi-4-piridona-3-carboxilo) es un nuevo fármaco antiviral con especial eficacia sobre los virus gripales que actúa inhibiendo la endonuclease cap-dependiente que precisan para su replicación. Es el primer representante de los denominados inhibidores de la proteína básica 2 (PB2) gripal. Ha mostrado eficacia frente a los virus gripales A y B y la mayoría de cepas de origen animal (gripe aviar). Los ensayos clínicos realizados en pacientes sanos de entre 12 y 64 años sin patologías y no hospitalizados (gripe leve) han mostrado una reducción de la duración de la sintomatología parecida a la obtenida por oseltamivir. Sin embargo baloxavir es un inhibidor de la replicación viral mucho más potente que este fármaco. Se ha mostrado como un fármaco seguro y bien tolerado. Se administra una sola dosis de 40-80 mg las primeras 48 horas del inicio de los síntomas. En estos ensayos se han detectado cepas con sensibilidad moderada (mutantes PA/I38T) en el 2,2% de la gripe A (H1N1)pdm09 y en el 9,7% de la gripe A (H3N2). A pesar de estos datos podría ser un buen fármaco para tratar la gripe leve o moderada, precisando de ensayos en gripe grave y pacientes con patologías crónicas para establecer su verdadera utilidad clínica


Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility


Assuntos
Humanos , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Antivirais/farmacocinética , Orthomyxoviridae/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Medicamentos Compostos contra Resfriado, Influenza e Alergia/farmacocinética , Resultado do Tratamento
13.
Toxicol Appl Pharmacol ; 365: 84-100, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639275

RESUMO

Current practices for evaluating the cumulative risk of thyroid-active chemical mixtures (perchlorate, thiocyanate, nitrate) focus on the inhibition of thyroidal iodide uptake via the sodium iodide symporter (NIS) as the mode of action for potency equivalence calculations. However, unlike perchlorate, thiocyanate presents additional modes of action within the thyroid that could contribute to the overall thyroid perturbation. We tested the hypothesis of whether assuming a single mode of action of thyroidal iodide uptake inhibition is sufficient for describing the observed dose-response relationship for thiocyanate and its effects on serum thyroxine levels. An interaction model was developed by linking a biologically based dose-response model for iodide and thyroid hormones to a thiocyanate physiologically based pharmacokinetic model. Each model, adapted from the literature, was restructured and recalibrated in a Bayesian framework for the current mode of actions study. For a chronic exposure scenario, NIS inhibition alone was found not to be sufficient to describe the dose-response relationship for thiocyanate. Inclusion of additional modes of action involving iodide flux across the thyroid membrane and inhibition of iodide organification via thyroid peroxidase showed only moderate improvements in capturing the dose-response at environmental thiocyanate doses of exposure and failed to capture trends at very high doses. Our findings emphasize the need for more mechanistic data for chronic exposure scenarios to characterize better the overall dose-response relationship for thiocyanate. Risk assessment approaches for thyroid-active chemical mixtures that rely on NIS inhibition as the single mode of action may over-predict the contribution of thiocyanate to thyroid disruption.


Assuntos
Simulação por Computador , Disruptores Endócrinos/toxicidade , Modelos Biológicos , Tiocianatos/toxicidade , Glândula Tireoide/efeitos dos fármacos , Tiroxina/metabolismo , Animais , Teorema de Bayes , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Disruptores Endócrinos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/metabolismo , Iodo/metabolismo , Masculino , Método de Monte Carlo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Medição de Risco , Tiocianatos/farmacocinética , Glândula Tireoide/metabolismo , Toxicocinética
14.
J Pharm Biomed Anal ; 162: 205-214, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30265980

RESUMO

S012-1332 is the first DNA ligase I inhibitor that demonstrated in vivo anti-breast cancer activity. The present study aimed to assess the in vivo pharmacokinetics of S012-1332 in rats and interpret them with in vitro findings. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S012-1332. Following oral administration, the absolute bioavailability was 7.04%. The absorption was prolonged which can be explained by low solubility in simulated gastric fluid and several folds higher solubility in simulated intestinal fluid. The effective permeability across the intestinal membrane in in situ single pass perfusion study for S012-1332 was 5.58 ± 1.83 * 10-5 cm/sec compared to 5.99 ± 0.65 * 10-5 cm/sec for carbamazepine, with no significant difference, indicating S012-1332 has high permeability. It was rapidly partitioning into plasma in blood, where it was stable. Plasma protein binding was moderate which may have attributed to the rapid distribution out of the vascular compartment. The pharmacokinetics of S012-1332 was characterized by extensive clearance as seen with rat liver and intestinal microsomes. In vitro results elucidate the in vivo pharmacokinetic data. These findings provide crucial information for further development of S012-1332 as anti-breast cancer agent.


Assuntos
Antineoplásicos/farmacocinética , DNA Ligase Dependente de ATP/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Disponibilidade Biológica , Cromatografia Líquida , DNA Ligase Dependente de ATP/metabolismo , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Inativação Metabólica , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Permeabilidade , Ligação Proteica , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
15.
Neuropharmacology ; 144: 327-336, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30439418

RESUMO

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARα signalling and show potential in the treatment of nicotine dependence.


Assuntos
Amidoidrolases/antagonistas & inibidores , Dopamina/metabolismo , Nicotina/farmacologia , Psicotrópicos/farmacologia , Recompensa , Amidoidrolases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento (Psicologia)/efeitos dos fármacos , Condicionamento (Psicologia)/fisiologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Masculino , Camundongos , Agonistas Nicotínicos/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
16.
J Pharm Biomed Anal ; 165: 198-206, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30553110

RESUMO

Stable isotope labeled (SIL) compounds have been commonly used as internal standards (IS) to ensure the accuracy and quality of liquid chromatography-mass spectrometry (LC-MS) bioanalytical assays. Recently, the application of SIL drugs and LC-MS assays to microdose absolute bioavailability (BA) studies has gained increasing attention. This approach can provide significant cost and time saving, and higher data quality compared to the accelerator mass spectrometry (AMS)-based method, since it avoids the use of radioactive drug, high-cost AMS instrumentation and complex measurement processes. It also eliminates potential metabolite interference with AMS-based assay. However, one major challenge in the application of this approach is the potential interference between the unlabeled drug, the microdose SIL drug, and the SIL-IS during LC-MS analysis. Here we report a convenient and cost-effective strategy to overcome the interference by monitoring the isotopic ion (instead of the commonly used monoisotopic ion) of the interfered compound in MS analysis. For the BMS-986205 absolute BA case study presented, significant interference was observed from the microdose IV drug [13C7,15N]-BMS-986205 to its SIL-IS, [13C7,15N, D3]-BMS-986205, since the difference of nominal molecular mass between the two compounds is only 3 mu, and there is a Cl atom in the molecules. By applying this strategy (monitoring the 37Cl ion for the analysis of the IS), a 90-fold reduction of interference was achieved, which allowed the use of a synthetically accessible SIL compound and enabled the fast progress of the absolute BA study. This strategy minimizes the number of stable isotope labels used for avoiding interference, which greatly reduces the difficulty in synthesizing the SIL compounds and generates significant time and cost savings. In addition, this strategy can also be used to reduce the MS response of the analyte, therefore, avoiding the detector saturation issue of LC-MS/MS assay for high concentration BMS-986205. A LC-MS/MS assay utilizing this strategy was successfully developed for the simultaneous analysis of BMS-986205 and [13C7, 15N]-BMS-986205 in dog plasma using [13C7,15N, D3]-BMS-986205 as the IS. The assay was successfully applied to a microdose absolute BA study of BMS-986205 in dogs. The assay was also validated in human plasma and used to support a human absolute BA study. The same strategy can also be applied to other compounds, including those not containing Cl or other elements with abundant isotopes, or other applications (e.g. selection of internal standard), and the applications were presented.


Assuntos
Acetamidas/análise , Cromatografia Líquida/métodos , Inibidores Enzimáticos/análise , Quinolinas/análise , Espectrometria de Massas em Tandem/métodos , Acetamidas/administração & dosagem , Acetamidas/farmacocinética , Animais , Disponibilidade Biológica , Cromatografia Líquida/economia , Análise Custo-Benefício , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Humanos , Marcação por Isótopo , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Espectrometria de Massas em Tandem/economia
17.
Bioorg Med Chem Lett ; 28(23-24): 3670-3673, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528979

RESUMO

This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fu < 0.03), high predicted hepatic clearance (rat CLhep > 65 mL/min/kg) and very short half-lives in vivo (t1/2 < 0.15 h). Removal of a nitrogen atom from this core generated a 2,8-diazaspiro[4.5]decanone core, harboring a new chiral center, as well as increased sp3 character. This new core demonstrated enantioselective inhibition of the individual PLD isoforms, enhanced free fraction (rat, human fu < 0.13), engendered moderate predicted hepatic clearance (rat CLhep ∼ 43 mL/min/kg), improved half-lives in vivo (t1/2 > 3 h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors.


Assuntos
Inibidores Enzimáticos/química , Fosfolipase D/metabolismo , Compostos de Espiro/química , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Meia-Vida , Humanos , Concentração Inibidora 50 , Fosfolipase D/antagonistas & inibidores , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade
18.
N Engl J Med ; 379(4): 352-362, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30044938

RESUMO

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).


Assuntos
Angioedemas Hereditários/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Calicreína Plasmática/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
19.
Comput Biol Chem ; 76: 151-160, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015176

RESUMO

A series of novel 1,3,4-oxadiazole-2-thione derivatives were designed, synthesized and evaluated for in vitro anticancer activity against breast cancer (MCF-7) cell line and thymidine phosphorylase. The synthesis of target compounds was performed by cyclization reaction using aromatic amines and carbon disulphide to get mannich bases. The synthesized compound 2j exhibited the most potent anticancer activity against MCF-7 cell line. Compounds 2d, 2j, 2o and 2h showed potent thymidine phosphorylase inhibitory activity. The SAR study revealed that the substitution of phenyl ring with electron withdrawing group at R1 position and less bulky amines group at R2 position of 1,3,4-oxadiazole-2-thione ring showed significant growth inhibitory activity. Further in silico ADMET properties of synthesized compounds were calculated along with molecular docking to study the binding mode of the compounds in the active site of thymidine phosphorylase (TP). The molecular docking studies showed that amines group have good binding interaction on active site residues of TP such as compounds 2j and 2o exhibited hydrogen bond interaction with amino acid residues GLY152, THR151 and HIS116 of thymidine phosphorylase (PDB ID: 1UOU). The result of biological activity and docking study revealed that amines group at R2 point of 1,3,4-oxadiazole-2-thione moiety is essential for anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Oxidiazóis/farmacologia , Tionas/farmacologia , Timidina Fosforilase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Domínio Catalítico , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacocinética , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/química , Tionas/farmacocinética , Timidina Fosforilase/química
20.
Bioorg Med Chem ; 26(12): 3707-3715, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29884581

RESUMO

To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (4a-4j) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives 4a-4j were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative 4a-4j showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound 4c exhibited higher potential in the series with IC50 0.251 ±â€¯0.012 µM (standard KH2PO4 4.317 ±â€¯0.201 µM). Lineweaver-Burk plots revealed that most potent derivative 4c inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds 4a-4j obey Lipinsk's rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound 4c interacts with Asp273, His317 and Arg166 amino acid residues.


Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Sulfadiazina/química , Tioureia/análogos & derivados , Fosfatase Alcalina/metabolismo , Animais , Sítios de Ligação , Domínio Catalítico , Bovinos , Desenho de Drogas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Depuradores de Radicais Livres/química , Meia-Vida , Intestinos/enzimologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tioureia/metabolismo , Tioureia/farmacocinética
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