RESUMO
BACKGROUND: Childhood chronic illness imposes financial burdens that may affect the entire family. OBJECTIVE: The aim was to assess whether adults living with children with 2 childhood chronic illnesses-asthma and diabetes-are more likely to forego their own medical care, and experience financial strain, relative to those living with children without these illnesses. RESEARCH DESIGN: 2009-2018 National Health Interview Survey. SUBJECTS: Adult-child dyads, consisting of one randomly sampled child and adult in each family. MEASURES: The main exposure was a diagnosis of asthma or diabetes in the child. The outcomes were delayed/foregone medical care for the adult as well as family financial strain; the authors evaluated their association with the child's illness using multivariable logistic regressions adjusted for potential confounders. RESULTS: The authors identified 93,264 adult-child dyads; 8499 included a child with asthma, and 179 a child with diabetes. Families with children with either illness had more medical bill problems, food insecurity, and medical expenses. Adults living with children with each illness reported more health care access problems. For instance, relative to other adults, those living with a child with asthma were more likely to forego/delay care (14.7% vs. 10.2%, adjusted odds ratio: 1.27; 95% CI: 1.16-1.39) and were more likely to forego medications, specialist, mental health, and dental care. Adults living with a child with diabetes were also more likely to forego/delay care (adjusted odds ratio: 1.76; 95% CI: 1.18-2.64). CONCLUSIONS: Adults living with children with chronic illnesses may sacrifice their own care because of cost concerns. Reducing out-of-pocket health care costs, improving health coverage, and expanding social supports for families with children with chronic conditions might mitigate such impacts.
Assuntos
Asma , Diabetes Mellitus , Humanos , Adulto , Estados Unidos , Criança , Acessibilidade aos Serviços de Saúde , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Asma/terapia , Doença Crônica , Inquéritos e QuestionáriosRESUMO
A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.
Assuntos
Azetidinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Memória/efeitos dos fármacos , Azetidinas/síntese química , Azetidinas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Even though evidence-based treatment for opioid use disorders (OUD) is effective, almost four in five Americans with OUD do not receive any form of treatment. The gap in access to evidence-based care, including treatment with medications for OUD, stems in part from barriers to change within the health care system. This paper includes nine key barriers that prevent access to evidence-based care, including stigma; inadequate clinical training; a dearth of addiction specialists; lack of integration of MOUD provision in practice; regulatory, statutory, and data sharing restrictions; and financial barriers. Action from a number of actors is urgently needed to address this crisis.
RESUMO
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
Assuntos
Benzimidazóis/antagonistas & inibidores , Benzimidazóis/química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Desenho de Fármacos , Canal de Potássio ERG1 , Eletroencefalografia/métodos , Eletromiografia/métodos , Canais de Potássio Éter-A-Go-Go/química , Humanos , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.
Assuntos
Acetamidas/síntese química , Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/síntese química , Pirimidinas/síntese química , Acetamidas/farmacocinética , Acetamidas/farmacologia , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Linhagem Celular , Clonagem Molecular , Cricetinae , Cricetulus , Haloperidol , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptor A2A de Adenosina/genética , Solubilidade , Relação Estrutura-Atividade , ÁguaRESUMO
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Assuntos
Acetamidas/farmacologia , Antagonistas do Receptor A2 de Adenosina , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Antagonistas do Receptor A1 de Adenosina , Animais , Avaliação Pré-Clínica de Medicamentos , Canais de Potássio Éter-A-Go-Go/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (K(i)<10 nM), and high selectivities over other melanocortin receptor subtypes.
Assuntos
Aminas/metabolismo , Álcoois Benzílicos/metabolismo , Cetonas/metabolismo , Piperazinas/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Aminas/síntese química , Aminas/química , Substituição de Aminoácidos , Animais , Álcoois Benzílicos/síntese química , Álcoois Benzílicos/química , Ligação Competitiva , Linhagem Celular , Humanos , Cetonas/síntese química , Cetonas/química , Ligantes , Melanocortinas/antagonistas & inibidores , Melanocortinas/metabolismo , Piperazinas/síntese química , Piperazinas/química , Ligação Proteica , Ratos , Receptor Tipo 4 de Melanocortina/química , Relação Estrutura-AtividadeRESUMO
Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers.
Assuntos
Desenho de Fármacos , Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Ciclização , Estrutura Molecular , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Receptor Tipo 4 de Melanocortina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacologia , Norepinefrina/química , Oxigênio/química , Inibidores da Captação Adrenérgica/química , Cloridrato de Atomoxetina , Citocromo P-450 CYP2D6/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Norepinefrina/metabolismo , Propilaminas/química , Propilaminas/farmacologia , Relação Estrutura-Atividade , Simportadores/químicaRESUMO
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Indanos/síntese química , Indanos/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Cloridrato de Atomoxetina , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indanos/química , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Propilaminas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Receptores LHRH/antagonistas & inibidores , Uracila/análogos & derivados , Uracila/síntese química , Animais , Citocromo P-450 CYP3A , Haplorrinos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Uracila/farmacocinéticaRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
Assuntos
Química Farmacêutica/métodos , Citocromo P-450 CYP3A/química , Íons , Receptores LHRH/antagonistas & inibidores , Uracila/análogos & derivados , Desenho de Fármacos , Hormônio Liberador de Gonadotropina/química , Humanos , Cinética , Modelos Químicos , Estrutura Molecular , Peptídeos/química , Estereoisomerismo , Relação Estrutura-Atividade , Uracila/químicaRESUMO
A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
Assuntos
Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Benzilaminas/síntese química , Benzilaminas/química , Células CACO-2 , Carcinoma Pulmonar de Lewis , Cristalografia por Raios X , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of piperazinephenethylamines were synthesized to study the contribution of a basic amine to binding affinity at the melanocortin-4 receptor. Several potent compounds from this series possessed subnanomolar K(i) values in a competition binding assay.
Assuntos
Fenetilaminas/química , Fenetilaminas/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Animais , Benzilaminas/metabolismo , Concentração Inibidora 50 , Cinética , Fenetilaminas/metabolismo , Piperazinas/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products. 7-Ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites. METHOD: 7-ethoxylcoumarin was incubated individually with human, monkey, dog and rat hepatocytes for 2 hr, metabolites were detected, identified and characterized using high resolution liquid chromagraphy - tandem mass spectrometry. RESULTS: Twenty-eight metabolites (M1 - M28) were detected and identified. O-deethylation, glucuronidation, sulfation, oxygenation, oxidative ring-opening, hydrogenation, glutathionation, dehydrogenation, cysteination, glucosidation, methylation, and hydrolysis were observed. At least sixteen metabolites not reported previously, were newly identified. M1 (O-deethylation, mono-oxygenation and glucuronidation), M3 (O-deethylation and glucuronidation), M5 (hydrolysis and mono-oxygenation), M14 (O-deethylation), M16 (hydrolysis), M22 (oxidative ring-opening and oxygenation) and M27 (monooxygenation) exhibited high mass spectrometric responses in human hepatocytes. M3, M5, M8, M13 (mono-oxygenation), M14, M16, M18 (O-deethylation and sulfation), M22 and M27 exhibited high mass spectrometric responses in monkey hepatocytes. M14, M16, M18, M20 (glutathionation and dehydrogenation) and M27 exhibited high mass spectrometric responses in dog hepatocytes. M1 (Odeethylation, mono-oxygenation and glucuronidation), M3, M5, M13, M14, M16, M17 (cysteination), M18, M20, and M22 exhibited high mass spectrometric responses in rat hepatocytes. CONCLUSION: Most of new metabolites via oxidative ring-opening and glutathionation were identified. Species differences in metabolism of 7-ethoxylcoumarin in hepatocytes were observed. The analysis of metabolites suggests that 7-ethoxylcoumarin may undergo 3,4-epoxidation responsible for formation of glutathione and its derived cysteine conjugates, carboxylic acid and its glucuronides, glucosides and sulfate.
Assuntos
Cumarínicos/metabolismo , Hepatócitos/metabolismo , Taxa de Depuração Metabólica , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cães , Feminino , Humanos , Macaca fascicularis , Masculino , Ratos , Especificidade da Espécie , Espectrometria de Massas em Tandem/métodosRESUMO
We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.
Assuntos
Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Memória/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Técnicas de Química Sintética , Proteínas da Membrana Plasmática de Transporte de Glicina/química , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Conformação Molecular , Permeabilidade , Pirazóis/química , Pirazóis/metabolismo , RatosRESUMO
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
Assuntos
Amidas/síntese química , Benzilaminas/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma Pulmonar de Lewis/complicações , Linhagem Celular , Cristalografia por Raios X , AMP Cíclico/metabolismo , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
Assuntos
Caquexia/tratamento farmacológico , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , beta-Alanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/etiologia , AMP Cíclico/metabolismo , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/complicações , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , beta-Alanina/síntese química , beta-Alanina/farmacocinética , beta-Alanina/farmacologiaRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.