RESUMO
Ion mobility spectrometry (IMS) is a reliable and sensitive technique for the detection and analysis of compounds at the trace level. Depending on the chemical composition of the sample, compounds may be positively or negatively charged to form different polarity ions and detected in positive or negative polarity of the electric field. In order to detect multiple threats simultaneously with miniaturized devices, using a single detection unit to achieve high resolving power and high sensitivity is important. In this work, a miniaturized drift tube with fast polarity switching capabilities integrated with Fourier deconvolution multiplexing techniques is proposed for the first time as a means to improve the performance of ion mobility spectrometry. The sensitivity and resolving power are improved compared to traditional polarity switching signal averaging data acquisition methods. The displayed device had a high resolving power up to 52 at a drift length of 41 mm and a drift tube voltage of 2 kV. Trinitrotoluene (TNT), methamphetamine (MA), benzene, toluene, methyl tert-butyl ether (MTBE), acetic acid, and methylene chloride were evaluated using the proposed fast polarity switching multiplexing spectrometer and exhibited satisfied performance.
RESUMO
MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Assuntos
Carbolinas/química , Carbolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Carbolinas/síntese química , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Assuntos
Piperazinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Haplorrinos , Camundongos , Obesidade/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10â¯000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
Assuntos
Inibidores Enzimáticos/química , Metionina Adenosiltransferase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/genética , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Homozigoto , Humanos , Metionina Adenosiltransferase/metabolismo , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Purina-Núcleosídeo Fosforilase/metabolismo , S-Adenosilmetionina/metabolismo , Relação Estrutura-AtividadeRESUMO
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Assuntos
Obesidade/tratamento farmacológico , Receptor Tipo 4 de Melanocortina/agonistas , Triazóis/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptor Tipo 4 de Melanocortina/genética , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Assuntos
Piperidinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Encéfalo/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Conformação Molecular , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Assuntos
Ligantes , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Humanos , Piperazina , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-AtividadeRESUMO
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Assuntos
Amidas/química , Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Pirrolidinas/química , Receptor Tipo 4 de Melanocortina/agonistas , Compostos de Espiro/química , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Relação Estrutura-AtividadeRESUMO
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Assuntos
Disfunção Erétil/tratamento farmacológico , Indanos/química , Indanos/uso terapêutico , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/metabolismo , Compostos de Espiro/química , Compostos de Espiro/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Ligação Proteica , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
The use of biochar to amend soil has been gaining increasing attention in recent years. In this study, the 15N tracer technique was used together with elemental analysis-stable isotope ratio analysis and gas isotope mass spectrometry to characterise biochar, soil, plant, and gas samples in order to explore the nitrogen transport mechanisms in the biochar-soil-plant-atmosphere system during the process of returning biochar to the soil (RBS). The results showed that the nitrogen retention rate of biochar was negatively correlated with the pyrolysis temperature during the preparation process, but was less affected by the pyrolysis atmosphere. In the RBS process, the migration of biochar nitrogen to plants was significantly greater than that of straw nitrogen, and it showed an overall decreasing trend with the increase in pyrolysis temperature, but was less influenced by the pyrolysis atmosphere. At temperatures of 300-500 °C, the pyrolysis atmosphere had a slightly smaller effect on the migration of biochar nitrogen to the air, plant, and soil system, and the pyrolysis temperature was much more important. However, the activation with CO2 gas at a higher temperature (600 °C) significantly enhanced the pore structure of biochar, particularly the structure of small pores; therefore, biochar prepared under a CO2 atmosphere at 600 °C reduces gaseous nitrogen emissions better than that under a N2 atmosphere. In the future, more pyrolysis conditions should be examined and their optimal combination should be further explored to reduce gaseous nitrogen emissions.
Assuntos
Pirólise , Solo , Carvão Vegetal , NitrogênioRESUMO
Recently, researchers have carried out a large number of studies on the adsorption of heavy metals by modified biochar, but there have been fewer explorations of the contributions and mechanisms of components in biochar composites on heavy metals adsorption. In this paper, the biochar was modified by Fe2+/Fe3+ and NaOH, and a further analysis of the adsorption of cadmium on the new biochar was conducted. It was found that (1) the adsorption capacity for cadmium of the modified biochar (M85) was 406.46 mg/g, which was 16 times that of the original biochar (C800); (2) the increased adsorption of cadmium onto the modified biochar had little correlation with the specific surface area, and the pure iron component was not the decisive factor for the huge adsorption capacity; and (3) the modified biochar was a kind of composite material with special construction, where the C-O-Fe structure that formed on its surface was the main reason for the sharp increase in adsorption. Among the iron components, iron oxides (Fe3O4, γ-Fe2O3 and Fe-O-Fe), iron-containing functional groups (-Fe-R-COOH and Fe-R-OH, etc.) and the mineral crystal XiFeYjOk reacted with the cadmium ion in aqueous solution to exchange, form complexes and precipitate, achieving the purpose of fixing the heavy metal. In addition, the aromatic structure C=Cπ can also adsorb Cd2+ to generate C=Cπ-Cd.
Assuntos
Cádmio/análise , Poluentes Químicos da Água/análise , Adsorção , Carvão VegetalRESUMO
Previous studies utilizing alpha-melanocyte-stimulating hormone (alpha-MSH) or the synthetic analog [Nle(4), D-Phe(7)] alpha-MSH have reported beneficial effects in animal models of ischemic stroke, with the latter studies suggesting melanocortin receptor subtype-4 (MC4R) activation as a protective mechanism. The present study directly addresses the hypothesis that MC4R activation may ameliorate ischemic brain injury by assessing the efficacy of a novel small molecule MC4R agonist RY767, administered in a pharmacokinetically guided and pharmacologically validated dosing regimen, in a rat stroke model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to 90-min tMCAO followed by 72 h of reperfusion. Treatments were i.p. pretreatment with MK-801 (15 min prior to occlusion, positive control), or combined i.v. and p.o. daily administrations of vehicle, dextrose (negative control) or RY767 in blinded fashion initiated 2 h after occlusion. Infarct volume in MK-801-treated rats (158.7 +/- 22.3 mm(3)) was reduced significantly compared to vehicle infarct volume (243.4 +/- 12.5 mm(3)), whereas infarct volumes in dextrose- (224.3 +/- 16.5 mm(3)) and RY767- (262.1 +/- 19.2 mm(3)) treated rats did not differ from vehicle infarct volume. These results indicate that selective MC4R activation provides no significant neuroprotection, as reflected by infarct volume, in a rat stroke model utilizing a 90-min ischemic insult.
Assuntos
Infarto da Artéria Cerebral Média/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Humanos , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções Intravenosas , Masculino , Fármacos Neuroprotetores/administração & dosagem , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , TelomeraseRESUMO
Biochar nitrogen is key to improving soil fertility, but the distribution of biochar nitrogen in the biomass-biochar-plant system is still unclear. To provide clarity, the 15N tracer method was utilised to study the distribution of biochar nitrogen in the biochar both before and after its addition to the soil. The results can be summarised as follows. 1) The retention rate of 15N in biochar decreases from 45.23% to 20.09% with increasing pyrolysis temperature from 400 to 800°C in a CO2 atmosphere. 2) The retention rate of 15N in biochar prepared in a CO2 atmosphere is higher than that prepared in a N2 atmosphere when the pyrolysis temperature is below 600°C. 3) Not only can biochar N slowly facilitate the adsorption of N by plants but the addition of biochar to the soil can also promote the supply of soil nitrogen to the plant; in contrast, the direct return of wheat straw biomass to the soil inhibits the absorption of soil N by plants. 4) In addition, the distribution of nitrogen was clarified; that is, when biochar was prepared by the pyrolysis of wheat straw at 400°C in a CO2 atmosphere, the biochar retained 45.23% N, and after the addition of this biochar to the soil, 39.99% of N was conserved in the biochar residue, 4.55% was released into the soil, and 0.69% was contained in the wheat after growth for 31days. Therefore, this study very clearly shows the distribution of nitrogen in the biomass-biochar-plant system.
RESUMO
We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.
Assuntos
Fosfatos/química , Ácidos Fosfóricos/química , Cristalização , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Fosfatos/farmacologiaRESUMO
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Assuntos
Depressores do Apetite/administração & dosagem , Depressores do Apetite/síntese química , Ingestão de Alimentos/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/síntese química , Receptor Tipo 4 de Melanocortina/metabolismo , Animais , Depressores do Apetite/metabolismo , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Ingestão de Alimentos/fisiologia , Humanos , Masculino , Modelos Moleculares , Oligopeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).
RESUMO
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.
Assuntos
Isoquinolinas/síntese química , Receptores da Corticotropina/agonistas , Tetra-Hidroisoquinolinas , Triazóis/síntese química , Animais , Ligação Competitiva , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Conformação Molecular , Ereção Peniana/efeitos dos fármacos , Ratos , Receptor Tipo 3 de Melanocortina , Receptor Tipo 4 de Melanocortina , Receptores de Melanocortina , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
RESUMO
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-ß-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic ß-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.