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1.
Eur J Med Chem ; 177: 47-62, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129453

RESUMO

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in ß- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in ß-position. This effect was attributed to the reduced basicity of ß-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.


Assuntos
Analgésicos/uso terapêutico , Benzazepinas/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hiperalgesia/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/toxicidade , Animais , Benzazepinas/síntese química , Benzazepinas/química , Benzazepinas/toxicidade , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
2.
Dalton Trans ; 48(28): 10464-10478, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31125040

RESUMO

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1-HL4) and four copper(ii) complexes 1-4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1-4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry. The ligands HL1-4 act as tridentate, the other two coordination places are occupied by two chlorido co-ligands. The organic ligands in 2 and 3 are bound tighter to copper(ii) when compared to related paullone ligands in 5 and 6. The new compounds show very strong cytotoxic activity against human colon adenocarcinoma doxorubicin-sensitive Colo 205 and multidrug resistant Colo 320 cancer cell lines with IC50 values in the low micromolar to nanomolar concentration range.


Assuntos
Antineoplásicos/farmacologia , Benzazepinas/química , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Indóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzazepinas/síntese química , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
3.
J Pharm Biomed Anal ; 172: 388-394, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31100536

RESUMO

Beclabuvir hydrochloride (BCV) is a marketed product for the treatment of hepatitis C viral infection. It contains functional groups such as indole, tertiary amine and amides. Forced degradation studies of BCV revealed different degradation profiles under photo and hydrogen peroxide oxidative conditions. Under the photo-oxidative degradation conditions, the tertiary amine on the piperazine ring was oxidized to form the degradants as the hydroxyl and des-methyl analogs of beclabuvir. However, under the oxidative condition using hydrogen peroxide, the indole ring was oxidized to form a typical kynuric degradant and two unexpected cyclohexyl rearranged diastereomeric degradants. The plausible mechanisms for the photo and hydrogen peroxide mediated oxidative degradation of beclabuvir hydrochloride are proposed.


Assuntos
Benzazepinas/química , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Indóis/química , Amidas/química , Aminas/química , Luz , Oxirredução , Raios Ultravioleta
4.
J Med Chem ; 62(1): 128-140, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30525590

RESUMO

The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts to identify agonists yielded catechol derivatives, mimicking dopamine, with suboptimal DMPK parameters and low selectivity over the D5 subtype. However, more recent efforts to identify ligands capable of activating the D1 receptor have made substantial progress with the identification of non-catechol agonists with suitable properties to progress to clinical studies. In addition, several research groups have identified positive allosteric modulators that offer new potential. Furthermore, structural studies have surprisingly uncovered two potential allosteric binding sites, the most characterized of which appears to be on intracellular loop 2 (ICL2). This review highlights the recent progress in the field, covering both orthosteric and allosteric modes of activation, discusses the elucidation of the allosteric binding sites, and summarizes the clinical development status of various compounds.


Assuntos
Receptores Dopaminérgicos/química , Regulação Alostérica , Animais , Benzazepinas/química , Benzazepinas/metabolismo , Sítios de Ligação , Agonistas de Dopamina/química , Agonistas de Dopamina/metabolismo , Humanos , Simulação de Acoplamento Molecular , Piperazina/análogos & derivados , Piperazina/metabolismo , Estrutura Terciária de Proteína , Receptores Dopaminérgicos/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-30594849

RESUMO

Benazepril, a common ACE inhibitor, widely used in the treatment of arterial hypertension and congestive heart failure. In this study, We evaluated the characteristics of the interaction between benazepril and BSA under the simulated physiological condition (pH7.4) through various spectroscopic and molecular docking methods. Fluorescence and absorption spectroscopy results showed benazepril quenched the intrinsic fluorescence of BSA through a combined dynamic and static quenching mechanism. The number of binding sites (n) and the binding constant (Kb) of benazepril-BSA complex were circa 1 and 6.81×103M-1 at 298K, respectively, indicating that the binding affinity between benazepril and BSA was moderate. The displacement experiments confirmed that benazepril binding to the site I of BSA, which was quite in accordance with molecular docking. The values of the Gibbs free energy (ΔG0), enthalpic change (ΔH0) and entropic change (ΔS0) were negative, verifying that van der Waals force and hydrogen bonding interaction played a predominant roles in the process of spontaneous bonding. Furthermore, a slight change of the conformation in BSA upon benazepril interaction was proved through SF, 3-DF and FTIR spectroscopy results.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Benzazepinas/química , Simulação de Acoplamento Molecular , Soroalbumina Bovina/química , Animais , Ligação Competitiva , Bovinos , Transferência de Energia , Interações Hidrofóbicas e Hidrofílicas , Cinética , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
6.
ChemMedChem ; 13(23): 2522-2529, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30312542

RESUMO

The 4-benzylpiperidine moiety is a central structural element of potent N-methyl-d-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated ω-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7 a-c and one butyraldehyde 7 d bearing a fluorine atom and an ω-phenyl moiety were prepared in 3- to 7-step syntheses. Compounds 7 a-d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety. Although benzoxazol-2-ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3-(fluoroalkyl)-substituted tetrahydro-1H-3-benzazepine (Ki =239 nm). However, high GluN2B affinity was obtained for the tetrahydro-5H-benzo[7]annulen-7-amines 12 a-c (Ki =17-30 nm). Docking studies resulted in the same binding pose for 12 a as for the lead compound Ro 25-6981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4-benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro-3-benzazepines and -benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit.


Assuntos
Aminas/química , Aminas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Alquilação , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Halogenação , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Tomografia por Emissão de Pósitrons , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Xenopus
7.
Nat Prod Rep ; 35(12): 1347-1382, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-30024006

RESUMO

Covering: 1969 to 2018 Azepinoindole natural products can be broadly classified as being of monoterpenoid or non-monoterpenoid origin. The non-monoterpenoid azepinoindoles have not received as much attention in the literature as their more revered monoterpenoid counterparts. In this review, an overview of all non-monoterpenoid azepinoindoles is provided. Various biological and chemical aspects are discussed, including their isolation, biosynthesis and the elegant total synthesis studies that have been inspired by these alkaloids.


Assuntos
Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Benzazepinas/química , Benzazepinas/isolamento & purificação , Benzodioxóis/isolamento & purificação , Técnicas de Química Sintética , Alcaloides de Claviceps/síntese química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Lignanas/biossíntese , Lignanas/isolamento & purificação , Estrutura Molecular , Monoterpenos , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/isolamento & purificação
8.
Bioorg Chem ; 80: 480-491, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29990896

RESUMO

A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date.


Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Dopaminérgicos/química , Dopaminérgicos/farmacologia , Receptores Dopaminérgicos/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Benzazepinas/síntese química , Dopaminérgicos/síntese química , Humanos , Masculino , Ligação Proteica , Ratos Sprague-Dawley , Tetra-Hidroisoquinolinas/síntese química
9.
Eur J Med Chem ; 151: 557-567, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29656199

RESUMO

Substituted norbenzomorphans are known to display high affinity and selectivity for the two sigma receptor (σR) subtypes. In order to study the effects of simplifying the structures of these compounds, a scaffold hopping strategy was used to design several novel sets of substituted isoindolines, tetrahydroisoquinolines and tetrahydro-2-benzazepines. The binding affinities of these new compounds for the sigma 1 (σ1R) and sigma 2 (σ2R) receptors were determined, and some analogs were identified that exhibit high affinity (Ki ≤ 25 nM) and significant selectivity (>10-fold) for σ1R or σ2R. The preferred binding modes of selected compounds for the σ1R are predicted by modeling studies, and the nature of substituents on the aromatic ring and the nitrogen atom of the bicyclic skeleton appears to affect the preferred binding orientation of σ1R-preferring ligands.


Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Isoindóis/química , Isoindóis/farmacologia , Receptores sigma/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade
10.
Bioorg Med Chem ; 26(9): 2686-2690, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29496415

RESUMO

Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin.


Assuntos
Fármacos Antiobesidade/síntese química , Benzazepinas/síntese química , Fármacos Antiobesidade/química , Benzazepinas/química , Técnicas de Química Sintética/métodos , Ciclização , Estereoisomerismo
11.
Eur J Med Chem ; 147: 194-204, 2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29438888

RESUMO

BuChE inhibitors play important roles in treatment of patients with advanced Alzheimer's disease (AD). A series of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one derivatives were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Some derivatives showed selective BuChE inhibitory activity, which was influenced by the volumes of the substituted groups at the C6 position and halogen substituents at the benzene ring of tricyclic scaffold. Among them, compounds 3f and 3o with dihalogen and 6-ethyl substituent showed the most potent activity (IC50 = 2.95, 2.04 µM, and mixed-type, non-competitive inhibition against BuChE, respectively). Eutomer (6R)-3o exhibited better BuChE inhibitory activity than (6S)-3o. Compound 3o exhibited nontoxic, good ADMET properties, and remarkable neuroprotective activity. Docking studies revealed the same binding orientation within the active site of target enzyme. Compound 3o was nicely bound to BuChE via three hydrogen bonds, one Alkyl interaction and three Pi-Alkyl interactions. The selective BuChE inhibitors had a potential use in progressive neurodegenerative disorder.


Assuntos
Benzazepinas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Animais , Benzazepinas/síntese química , Benzazepinas/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Ratos , Relação Estrutura-Atividade
12.
Expert Opin Pharmacother ; 19(3): 223-231, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29376439

RESUMO

INTRODUCTION: Type 2 diabetes (T2DM) is associated with significant morbidity and mortality. Obesity is one of the main risk factors for T2DM and its management requires a multidisciplinary approach, which may include pharmacotherapy. AREAS COVERED: In this paper, data on efficacy, tolerability and safety of FDA-approved pharmacotherapies for obesity (orlistat, phentermine/topiramate extended-release, lorcaserin, bupropion sustained release/naltrexone sustained release and liraglutide) are reviewed, focusing on individuals with type 2 diabetes. EXPERT OPINION: Obesity is the major pathophysiologic driver of T2DM; conversely 5-10% weight loss leads to significant improvement in glycemic control, lipids and blood pressure. Weight loss maintenance is difficult with lifestyle interventions alone and may require adjunctive therapies. There is good evidence for the efficacy and tolerability of approved anti-obesity pharmacotherapies in individuals with T2DM, with current cardiovascular safety data being most favorable for liraglutide, orlistat and lorcaserin. Given the link between obesity and T2DM, a weight-centric therapeutic approach including use of weight reducing anti-diabetic therapies, and anti-obesity pharmacotherapies is both intuitive and rational to improve glycemic and other metabolic outcomes in patients with T2DM.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Obesidade/tratamento farmacológico , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Benzazepinas/química , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Ensaios Clínicos como Assunto , Composição de Medicamentos , Humanos , Lactonas/química , Lactonas/farmacologia , Lactonas/uso terapêutico , Liraglutida/química , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Orlistate , Fentermina/química , Fentermina/farmacologia , Fentermina/uso terapêutico , Perda de Peso/efeitos dos fármacos
13.
Bioorg Med Chem ; 26(4): 977-983, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29254893

RESUMO

A two-step process to synthesize racemic lorcaserin was developed from 2-(4-chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4-chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin.


Assuntos
Benzazepinas/química , Alilamina/química , Alumínio/química , Benzazepinas/síntese química , Brometos/química , Catálise , Cloretos/química , Ciclização , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Temperatura , Compostos de Zinco/química
14.
Bioorg Med Chem ; 26(2): 501-508, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29254894

RESUMO

The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2-) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.


Assuntos
Benzazepinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Benzazepinas/síntese química , Benzazepinas/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
15.
Artigo em Inglês | MEDLINE | ID: mdl-29128602

RESUMO

The selection and validation of bioactive compounds require multiple approaches, including in-depth analyses of their biological activity in a whole-animal context. We exploited the sea urchin embryo in a rapid, medium-scale range screening to test the effects of the small synthetic kinase inhibitor kenpaullone. We show that sea urchin embryos specifically respond to this molecule depending on both dose and timing of administration. Phenotypic effects of kenpaullone are not immediately visible, since this molecule affects neither the fertilization nor the spatial arrangement of blastomeres at early developmental stages. Nevertheless, kenpaullone exposure from the beginning of embryogenesis profoundly perturbs specification, detachment from the epithelium, and migration of the primary mesenchyme cells, thus affecting the whole embryonic epithelial mesenchymal transition process. Our results reaffirm the sea urchin embryo as an excellent and sensitive in vivo system, which provides straightforward and rapid response to external stimuli.


Assuntos
Benzazepinas/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Indóis/farmacologia , Paracentrotus/embriologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzazepinas/química , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Indóis/química , Estrutura Molecular
16.
J AOAC Int ; 101(4): 1009-1013, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28882197

RESUMO

A simple, specific, and rapid kinetic study of benazepril (BNZ) hydrolysis was developed and validated using HPLC. BNZ was degraded using 0.1 N sodium hydroxide at room temperature to produce benazeprilat, which is an active metabolite of BNZ and acts as an angiotensin-converting enzyme inhibitor. Analysis was carried out using an Athena C18 column (4.6 × 250 mm, 5 µm particle size). The mobile phase consists of a mixture of phosphate buffer (pH 4.5) and acetonitrile (53 + 47, v/v) at a flow rate of 1 mL/min. UV detection was accomplished at 242 nm using moexipril as the internal standard. The method was validated according to International Conference on Harmonization guidelines, and the calibration curve was linear over the range 10-100 µg/mL, with acceptable accuracy and precision. Kinetic profiling of the hydrolysis was shown to follow pseudo-first-order kinetics. The method was applied to the assay of BNZ in combined dosage form with no interference from other ingredients. The obtained results were statistically compared with those of the official method, showing no significant difference.


Assuntos
Benzazepinas/análise , Benzazepinas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Acetonitrilos/química , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/química , Benzazepinas/química , Tampões (Química) , Calibragem , Cápsulas/análise , Cromatografia Líquida de Alta Pressão/normas , Concentração de Íons de Hidrogênio , Hidrólise , Inativação Metabólica , Cinética , Reprodutibilidade dos Testes , Hidróxido de Sódio/química , Tetra-Hidroisoquinolinas/análise
17.
Med Chem ; 14(4): 400-408, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28969573

RESUMO

BACKGROUND: Benzazepines received great attention in the field of medicinal chemistry since this scaffold has been recognized to belong to the important family of privileged templates. More specifically, the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) is used as a core structure in a variety of constrained therapeutic peptide (turn) mimetics.Most of the synthetic approaches towards this template have focused on cyclizations which form the central 7-membered azepine ring. OBJECTIVE: Previous investigations in our group allowed an expansion of the substitution patterns in the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and 5 of the azepinone ring system, but also to 1-aryl substituted compounds. These were the only trisubstituted analogues obtained to date. To introduce an additional point of diversification and conformational constraint useful for peptide mimicry, one can use bifunctional substrates in the Ugi reaction as reported in the present manuscript. METHOD: The 1-carboxamido-substituted Aba scaffold has been synthesized via the Ugi-3CR reaction starting from N-Phth-protected 2-formyl-L-Phe-OH with a set of amine and isocyanide derivatives. The most suited reaction conditions were applied, involving preformation of the imine in MeOH (0.1 M) in the presence of anhydrous Na2SO4 during 2 hours at room temperature, followed by the addition of an equimolar quantity of isocyanide prior to heating the reaction mixture at 80 °C for 20 hours, using sealed vial reaction conditions. RESULTS: The substituted Aba scaffolds were isolated in moderate yields (and diastereomeric ratio). This is due to the requirement for a double N-phthaloyl protection of the bifunctional building block, which prevents the use of an excess of amine reagent to drive the reaction conversion to completion, and some starting substrate always remains. Despite the moderate yields, the methodology is efficient since it only requires a limited number of synthetic steps in a final one-pot reaction. In most cases, the diastereomers could be separated by preparative RP-HPLC or via silica gel column chromatography. This is interesting from a medicinal chemistry point of view, since access is provided to the individual diastereomers. CONCLUSION: We have developed an efficient and useful one-pot strategy to access 1-substituted 4- aminobenzazepinone (Aba) derivatives via the Ugi-3CR reaction. To the best of our knowledge, these scaffolds are only accessible through the presented methodology. The obtained structural complexity, as well as the substitution versatility of these trisubstituted scaffolds, will allow their use in various biological applications.


Assuntos
Benzazepinas/síntese química , Benzazepinas/química , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Estereoisomerismo
18.
J Med Chem ; 60(23): 9838-9859, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29131958

RESUMO

Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system.


Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Desenho de Fármacos , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Benzazepinas/síntese química , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Hormônios Peptídicos/antagonistas & inibidores , Hormônios Peptídicos/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Eur J Med Chem ; 141: 567-583, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102177

RESUMO

Novel tetrahydro-5H-benzo[e][1,4]diazepin-5-ones, several of them, containing the quinoline pharmacophore, were synthesized via a Schmidt rearrangement from their corresponding 1,2,3,4-tetrahydro-4-quinolones mediated by the NaN3/H2SO4 reaction conditions. Twelve of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where compound 24a presented a remarkable activity against 58 of the 60 cancer cell lines, with the most important GI50 values ranging from 0.047 to 8.16 µM and LC50 values ranging from 9.4 to > 100 µM. Additionally, some of them were evaluated as antimalarial, antitrypanosomal and antileishmanial agents. The best antimalarial response was observed for compound 22g with an EC50 = 13.61 µg/mL for Plasmodium falciparum, while compound 24d exhibited high activity against Trypanosoma cruzi. and Leishmania (V) panamensis with EC50 = 2.78 µg/mL and 3.35 µg/mL respectively.


Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Benzazepinas/farmacologia , Leishmania/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Benzazepinas/síntese química , Benzazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
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