RESUMO
Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,ß-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.
Assuntos
Compostos Azo/química , Pirrolidinas/síntese química , Tiossemicarbazonas/química , Reação de Cicloadição , Estrutura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMO
Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.
Assuntos
Benzamidas/química , Pirimidinas/química , Receptores de Glucagon/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Células Cultivadas , Cães , Ligantes , Conformação Molecular , Estrutura Molecular , Oxirredução , Ligação Proteica/efeitos dos fármacos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Propionatos/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Físico-Química , Cães , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Haplorrinos , Humanos , Fígado/citologia , Camundongos , Estrutura Molecular , Propionatos/administração & dosagem , Propionatos/síntese química , Ratos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-AtividadeRESUMO
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Assuntos
Ativadores de Enzimas/química , Glucoquinase/metabolismo , Pirimidinonas/síntese química , Regulação Alostérica , Motivos de Aminoácidos , Animais , Sítios de Ligação , Modelos Moleculares , Pirimidinonas/química , RatosRESUMO
A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Pirazóis/química , Receptores de Glucagon/antagonistas & inibidores , Animais , Química Farmacêutica/métodos , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Éter/química , Glucagon/química , Glucose/química , Humanos , Cinética , Modelos Químicos , Peso Molecular , Ratos , TemperaturaRESUMO
Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.
Assuntos
Desenho de Fármacos , Glucoquinase/química , Hipoglicemiantes/síntese química , Indazóis/química , Pirazinas/síntese química , Pirazóis/química , Piridinas/química , Administração Oral , Animais , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase/metabolismo , Teste de Tolerância a Glucose , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Indazóis/síntese química , Indazóis/farmacocinética , Indazóis/uso terapêutico , Insulina/metabolismo , Cinética , Ligação Proteica , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Técnicas de Química Sintética/métodos , Xantonas/química , Xantonas/síntese química , Linhagem Celular Tumoral , Humanos , Estereoisomerismo , Especificidade por SubstratoRESUMO
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.
Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Fluoroquinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Camundongos , Inibidores da Topoisomerase II/químicaRESUMO
BACKGROUND: Preoperative computed tomography (CT) guided microcoil localization is a common method for small lung nodules before video-assisted thoracoscopic surgery (VATS). However, this method still has some limitation such as complicated operation and slight complications. We have optimized the original method. The purpose of this study was to investigate the clinical value of this optimized method. METHODS: 35 pulmonary nodules from 31 patients between September 2018 and January 2019 were localized by the optimized method before VATS. The success rate, complications, pathological results and localization operations related data were statistically analyzed. RESULTS: The success rate of localization was 97.1%, and the success rate of VATS removal was 100%. The average operation time was 10.1 min (5 min-31 min), and the average time required for resection of lesions was 38.2 min (10 min-100 min). During the surgery, the microcoil of one patient was found to be dislocated and retracted into the chest wall. A puncture needle was inserted intolung tissue from the chest wall puncture point after the lung was inflated, and then the pulmonary nodule were successfully located and removed. A minor pneumothorax occurred in 3 patients, but no closed drainage was needed. Three patients developed intrapulmonary hematoma. The pathological results of 35 pulmonary nodules included 15 well-differentiated adenocarcinoma, 7 carcinoma in situ, 5 microinvasive adenocarcinoma, 4 atypical adenomatoid hyperplasia, 2 intrapulmonary lymph node hyperplasia, 2 inflammatory nodules. CONCLUSIONS: For small pulmonary nodules requiring thoracoscopic surgery, the optimized computed tomography-guided pulmonary nodule microcoil localization technique is convenient, safe and effective, and worthy of promotion to use.
Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Linfonodos/diagnóstico por imagem , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/cirurgia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
BACKGROUND: Localization of multiple small lung nodules is the technical difficulty of minimally invasive operation resection. However, there are few clinical studies on the preoperative localization of multiple small lung nodules. This study was designed to evaluate the clinical value of preoperative computed tomography (CT) guided microcoil localization for multiple small lung nodules compared with single small lung nodule before video-assisted thoracoscopic surgery (VATS). METHODS: A retrospective analysis of the clinical data of 235 patients with preoperative pulmonary nodules microcoil localization was performed. According to whether the nodules were single, they were divided into single nodule group (184 cases) and multiple nodules group (51 cases) (multiple nodules group). The single nodule group was positioned under CT-guided conventional methods. The multiple nodules group were CT guided localized by microcoil in batches according to priority before VATS. The success rate, complications, pathological results and localization operations related data were statistically analyzed. RESULTS: The success rate of localization in multiple nodule groups was 90.2%, there was no significant difference compared with the single nodule group (90.2% vs 94.6%, P=0.205). The occurrence rate of pneumothorax in multiple nodule group and single nodule group was no statistical difference (21.6% vs 14.1%, P=0.179), however, the operation time in the multiple nodule group was significantly longer than the single nodule group [(30.6±6.6) min vs (19.9±7.4) min, P=0.000]. There were no serious complications such as massive hemoptysis, air embolism or hemothorax. There was no conversion to thoracotomy due to failure of localizing the nodules during operation. Sub-lobectomy was the main method of operation. The majority of postoperative pathologies were non-invasive carcinomas. CONCLUSIONS: For multiple small lung pulmonary nodules requiring thoracoscopic surgery, according to certain strategies, preoperative CT-guided localized by microcoil in batches according to priority before VATS is safe and effective, and worthy of promotion.
Assuntos
Neoplasias Pulmonares/cirurgia , Nódulos Pulmonares Múltiplos/cirurgia , Período Pré-Operatório , Cirurgia Assistida por Computador , Cirurgia Torácica Vídeoassistida/instrumentação , Tomografia Computadorizada por Raios X , Carga Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
Assuntos
Descoberta de Drogas , Dor/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Solubilidade , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Imidazóis/química , Piridinas/química , Pirrolidinas/química , Animais , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Cães , Dislipidemias/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Knockout , Piridinas/farmacocinética , Piridinas/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de LDL/genética , Células Sf9 , Spodoptera , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[structure: see text] The multistep synthesis of a calixarene joined to a second calixarene via a long spacer is described. Since each calixarene bears multiple galactose-based units (known to bind strongly to rat hepatoma cells), there existed the possibility of cross-linking the cancer cells into a network. The compounds did not serve this purpose, a fact potentially correctable by adjusting or rigidifying the spacer. Formation of a "cancer net" around a solid tumor remains a viable approach to retarding growth and/or inhibiting metastasis.
Assuntos
Antineoplásicos/síntese química , Calixarenos/síntese química , Animais , Antineoplásicos/farmacologia , Calixarenos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Galactose/química , Estrutura Molecular , RatosRESUMO
The addition of the SuperQuat enolate to five- and six-membered heterocyclic tert-butyl sulfinimines led to a high syn-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to ß-amino esters and amides in a facile manner.
Assuntos
Aminoácidos/síntese química , Iminas/química , Compostos de Sulfônio/química , Amidas/química , Aminoácidos/química , Técnicas de Química Combinatória , Estrutura Molecular , EstereoisomerismoRESUMO
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic ß-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/síntese química , Glucoquinase/metabolismo , Hepatócitos/metabolismo , Hipoglicemiantes/síntese química , Imidazóis/síntese química , Ácidos Nicotínicos/síntese química , Sítio Alostérico , Animais , Glicemia/metabolismo , Cães , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Haplorrinos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Masculino , Modelos Moleculares , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Descoberta de Drogas , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Área Sob a Curva , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , RatosRESUMO
Functionalized alpha-amino acid building blocks have been prepared in good yield with high regiocontrol and preservation of stereochemistry via iridium-catalyzed borylation of suitably protected aromatic alpha-amino acid derivatives. The utility of these systems in peptide couplings and Suzuki reactions has been demonstrated.
Assuntos
Aminoácidos Aromáticos/síntese química , Peptídeos/síntese química , Aminoácidos Aromáticos/química , Catálise , Técnicas de Química Combinatória , Irídio/química , Estrutura Molecular , Peptídeos/química , EstereoisomerismoAssuntos
Látex/química , Maleimidas/química , Propionatos/química , 1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , Ditiotreitol/química , Composição de Medicamentos , Látex/síntese química , Maleimidas/síntese química , Microscopia Confocal , Microscopia Eletrônica de Varredura , Microscopia de Contraste de Fase , Fosfatidilgliceróis/química , Propionatos/síntese químicaRESUMO
The nigellamine alkaloids are dolabellane diterpenes displaying potent lipid metabolism-promoting activity. Total synthesis of (+)- and (-)-nigellamine A2 has been accomplished. Absolute stereochemistry of synthetic nigellamine A2 was established through an intramolecular asymmetric allylic alkylation using a Pd(phosphinooxazoline) catalyst. Other notable transformations include a radical alkynylation, a diastereoselective Nozaki-Hiyama-Kishi cyclization, and a regio- and stereoselective catalytic epoxidation. On the basis of X-ray crystallographic analysis of an optically active intermediate, we have confirmed the assigned absolute stereochemistry of the natural product. Minor modifications of the synthetic sequence outlined here should provide access to the other nigellamine alkaloids.