RESUMO
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiazóis/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
BACKGROUND: We hypothesized that the addition of a third-level trauma activation would improve outcomes by formalizing an evaluation process for patients in need of urgent evaluation who did not meet the criteria for full or partial trauma alert activation. METHODS: Admission records for all trauma patients admitted between 2000 and 2021 were obtained. The gamma alert trauma activation was implemented in 2011. A washout period of 6 months was used to account for adjustment to the new protocol. Propensity score matching was performed based on ISS scores, age, injury mechanism, and best-validated comorbidities to create a balanced patient distribution. Patients with missing data were excluded from this study. The association between era and outcomes was determined using logistic and linear regression analyses. RESULTS: The matched cohort was well balanced (SMD <.1, all balanced covariates) and included 18,572 patients. Patients in the gamma alert era had decreased ED dwell time, hospital length of stay, and intensive care unit (ICU) length of stay. Readmission rates and rates of upgrade to ICU status were reduced in the gamma alert era. This era was also associated with lower rates of renal failure, UTI, and pneumonia. There was no significant difference in mortality following implementation of the gamma alert. DISCUSSION: Implementation of the gamma alert was associated with an improvement in ED dwell times, fewer unplanned admissions to the ICU, decreased readmissions, and a reduction in other in-hospital events. We believe that this reflects improved triage of patients to the ICU and more effective care of trauma patients.
Assuntos
Centros de Traumatologia , Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Unidades de Terapia Intensiva , Escala de Gravidade do Ferimento , Análise de Regressão , Tempo de Internação , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/terapiaRESUMO
OBJECTIVE: Psoas muscle size is a reliable marker of sarcopenia and frailty that correlates with adverse outcomes after cardiac surgery. However, its use in mitral and minimally invasive cardiac surgery is lacking. We sought to determine whether frailty, as measured by psoas muscle index, increases surgical risk for minimally invasive mitral valve surgery. METHODS: Patients undergoing isolated minimally invasive mitral surgery via right minithoracotomy were identified. Patients who underwent maze, tricuspid intervention, and those who were emergent were excluded. Total psoas muscle area was calculated using the average cross-sectional area at the L3 vertebra on computed tomography scan and indexed to body surface area. Sarcopenia was defined as <25th gender-specific percentile. Patients were stratified by sarcopenia status and outcomes compared. RESULTS: Of 287 total patients, 192 patients met inclusion criteria. Sarcopenic patients were 6 years older (66 vs 60 years, P = 0.01), had lower preoperative albumin levels (4.0 vs 4.3 g/dL, P < 0.001), and had higher Society of Thoracic Surgeons risk of morbidity/mortality (13.1% vs 9.0%, P = 0.003). Operative major morbidity or mortality was 6.4% versus 5.5% (P = 0.824), while the 1-year mortality rate was 2.1% versus 0% (P = 0.08). After risk adjustment, psoas index did not predict operative morbidity or mortality. However, sarcopenia was associated with higher odds of readmission (odds ratio = 0.74, P = 0.02). CONCLUSIONS: Contrary to other cardiac operations, for patients undergoing isolated minimally invasive mitral valve surgery, sarcopenia was not associated with increased perioperative risk except for higher readmission rates. Minimally invasive surgical approaches should be strongly considered as the approach of choice in frail patients.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Fragilidade , Sarcopenia , Humanos , Fragilidade/complicações , Fragilidade/epidemiologia , Valva Mitral/cirurgia , Fatores de Risco , Estudos Retrospectivos , Sarcopenia/complicações , Sarcopenia/epidemiologia , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate short-term outcomes and statewide practice patterns of prophylactic left atrial appendage ligation (P-LAAL) in coronary artery bypass grafting (CABG) patients without pre-operative atrial fibrillation (AF). METHODS: Adult patients who underwent an on-pump CABG (2017 - 2023) within a regional collaborative were identified. Patients with a history of AF, previous cardiac surgery, or non-device based LAAL were excluded. Patients were stratified by LAAL status and were propensity score matched. Univariable analysis was used to compare short-term clinical outcomes. RESULTS: Of 16,547 patients examined, 442 underwent P-LAAL. The propensity score matched cohort (439 P-LAAL, 439 No P-LAAL) was compared and had no significant differences in pre-operative CHA2DS2-VASc scores or operative variables. The P-LAAL group had longer cross clamp time (82 vs 76 minutes, p=0.001), ICU hours (72 vs 66, p=0.001), length of stay (6.0 vs 6.0 days, p=0.010), increased post-operative AF (35% vs 24%, p<0.001), and more discharge on anticoagulation (17% vs 8.2%, p<0.001). There were no significant differences in post-operative stroke (1.1% vs 2.1%, p=0.423), readmission (13% vs 9.6%, p=0.118), operative mortality (2.5% vs 1.6%, p=0.480), or readmission for thrombotic or bleeding complications (0.7% vs 1.1%, p=0.724). Hospitalization costs were significantly higher for P-LAAL patients ($43,478 vs $40,645, p<0.001). The rate of P-LAAL during CABG increased from 1.61% (2017) to 5.65% (2023) (p<0.001). CONCLUSIONS: Despite higher rates of post-operative AF, discharge on anticoagulation, and hospitalization costs in patients undergoing P-LAAL during CABG, there was no difference in short-term clinical endpoints including stroke and operative mortality.
RESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Trauma scoring systems were created to predict mortality and enhance triage capabilities. However, efficacy of scoring systems to predict mortality and accuracy of originally reported severity thresholds remains uncertain. A single-center, retrospective study was conducted at University of Virginia (UVA), an American College of Surgeons verified Level I trauma center. We compared four scoring systems: MGAP (Mechanism, Glasgow Coma Scale, Age, and arterial pressure), Injury Severity Score (ISS), New Injury Severity Score (NISS), and Trauma Related Injury Severity Score (TRISS) to predict in-hospital mortality and disposition from the emergency department to higher acuity level of care including mortality (i.e. operating room, intensive care unit, morgue) versus standard floor admission using area under the curve (AUC) for receiver operating characteristic analysis. Second, we examined sensitivity of these scores at standard thresholds to determine if adjustments were needed to minimize under-triage (sensitivity ≥95%). TRISS was the best predictor of mortality in a cohort of n = 16,265 with AUC of 0.920 (95% CI: 0.911-0.929, p<0.0001), followed by MGAP with AUC of 0.900 (95% CI: 0.889-0.911, p<0.0001), and finally ISS and NISS (0.830 (95% CI: 0.814-0.847) and 0.827 (95% CI: 0.809-0.844) respectively). NISS was the best predictor of high acuity disposition with an AUC of 0.729 (95% CI: 0.721-0.736, p<0.0001), followed by ISS with AUC of 0.714 (95% CI: 0.707-0.722, p<0.0001), and finally TRISS and MGAP (0.673 (95% CI: 0.665-0.682) and 0.613 (95% CI: 0.604-0.621) respectively (p<0.0001). At historic thresholds, no scoring system displayed adequate sensitivity to predict mortality, with values ranging from 73% for ISS to 80% for NISS. In conclusion, in the reported study cohort, TRISS was the best predictor of mortality while NISS was the best predictor of high acuity disposition. We also stress updating scoring system thresholds to achieve ideal sensitivity, and investigating how scoring systems derived to predict mortality perform when predicting indicators of morbidity such as disposition from the emergency department.
Assuntos
Hospitais , Ferimentos e Lesões , Humanos , Escala de Gravidade do Ferimento , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Índices de Gravidade do Trauma , Ferimentos e Lesões/terapiaRESUMO
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Naftiridinas/síntese química , Naftiridinas/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/química , Inibidores de Integrase de HIV/química , Estrutura Molecular , Naftiridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.
Assuntos
Inibidores de Integrase de HIV/química , Integrase de HIV , Pirazinas/química , Linhagem Celular Tumoral , Integrase de HIV/fisiologia , Inibidores de Integrase de HIV/farmacologia , Humanos , Pirazinas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/virologiaRESUMO
We examined financial data from a University Level I Trauma Center from 1994 to 2014. We sought to investigate the hypothesis that lower injury severity correlates with increased profitability. We examined data from July 1994 to December 2014. This included hospital charges, Medicare cost data, final reimbursement, and payor source. Patients were separated into Injury Severity Score (ISS) groupings: 0 to 9, 10 to 14, 15 to 24, >24, and >14. Mean and standard deviation of mean are reported. We had complete data on 27,582 patients. Overall profit per case when subtracting costs from reimbursements was $1,932/case (total profit in unadjusted dollars = $53,475,828 or $2,673,791/year). When examined by ISS, profitability was significantly different between ISS 0 to 14 and 15 to 24, and > 24. When charge data were examined, the average loss per case was -$31,313 for the 27,582 patient data set. When using cost, and not charge data, overall trauma care had a positive margin. Severely injured patients (ISS > 14) were the most profitable, with a significantly higher profit per case than all other groupings. Only through examination of cost data can realistic determinations of trauma center profitability be made. If only charge data had been examined in this study, the overall loss from the 20-year period would have been $863,675,166 and not a profit of $53,475,828.
Assuntos
Índice de Gravidade de Doença , Centros de Traumatologia/economia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , VirginiaRESUMO
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Naftiridinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Injeções Intravenosas , Naftiridinas/química , Naftiridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Thumb injuries during team roping have elements of both avulsion and crush, resulting in a poor prognosis for replantation success. PURPOSE: To review 19 cases of thumb amputation from team roping at our institution since 1983. STUDY DESIGN: Retrospective cohort study. METHODS: Cases were included in the study only if a microvascular repair of artery and vein was needed for the thumb to survive. Vein grafts were used to span the damaged vessel segment. Of the 19 thumb amputation cases, 15 attempts were made to replant the thumb. In the remaining four cases, patients had bone shortening and primary closure. The force of injury was calculated based on mechanism. RESULTS: Of the 15 attempts at replantation, only 5 (33%) were successful, despite meticulous technique. One patient subsequently had an emergency toe-to-thumb transfer after an unsuccessful replant, and the remaining nine underwent amputation. Nine of the 10 patients with failed replants had poor flow intraoperatively. In the group of patients younger than 15, the success was 3 of 5 (60%) and in the group 15 years or older the success was 2 of 10 attempts (20%.) Follow-up was available in 13 of the 15 cases of replanted thumbs. CONCLUSIONS: All patients were subjectively satisfied with their results, and all patients with successful replants and seven patients with no thumb returned to rodeo. Biomechanical analysis showed a huge amount of force and pressure, several times larger than that of ring avulsion injury, results when a steer pulls on the thumb.
Assuntos
Amputação Traumática/etiologia , Amputação Traumática/cirurgia , Traumatismos em Atletas/etiologia , Traumatismos em Atletas/cirurgia , Procedimentos Ortopédicos/métodos , Procedimentos de Cirurgia Plástica/métodos , Reimplante , Polegar/lesões , Polegar/cirurgia , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fluxo Sanguíneo Regional , Estudos Retrospectivos , Polegar/irrigação sanguínea , Dedos do Pé/transplante , Resultado do TratamentoRESUMO
The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
Assuntos
Desenho de Fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neuropeptídeos/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cães , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/metabolismo , Orexinas , Ratos , Ratos Sprague-Dawley , Distúrbios do Início e da Manutenção do Sono/metabolismoRESUMO
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexinâ 1 and orexinâ 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional inâ vivo activity in preclinical sleep models, and has advanced into phaseâ II clinical trials for the treatment of insomnia.
Assuntos
Hipnóticos e Sedativos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/síntese química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Descoberta de Drogas , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Vigília/efeitos dos fármacosRESUMO
Raltegravir is the first integrase strand transfer inhibitor approved for the treatment of HIV-1 infection. As the first agent in this new class of antiretroviral therapies, raltegravir has demonstrated safety and efficacy in treatment-naive as well as heavily pretreated HIV-infected patients failing therapy with multidrug-resistant virus. Raltegravir has a favorable drug interaction profile that permits both administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. Data through 96 weeks of follow-up in three phase III studies, protocol 021 (STARTMRK) in treatment-naive patients, and protocols 018 (BENCHMRK-1) and 019 (BENCHMRK-2) in treatment-experienced patients, demonstrated the potent and durable antiretroviral and immunologic effects and the favorable long-term safety profile of raltegravir in both treatment-naive and treatment-experienced patients. Raltegravir represents an important addition to the current armamentarium for the treatment of HIV infection.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Pirrolidinonas/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/síntese química , Antirretrovirais/administração & dosagem , Antirretrovirais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Pirrolidinonas/administração & dosagem , Pirrolidinonas/efeitos adversos , Pirrolidinonas/síntese química , Raltegravir Potássico , Resultado do TratamentoRESUMO
A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologiaRESUMO
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Assuntos
Azepinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Triazóis/farmacologia , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Receptores de Orexina , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Telemetria , Triazóis/síntese química , Triazóis/farmacocinética , Vigília/efeitos dos fármacosRESUMO
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 6 is active against replication of HIV with a CIC(95) of 0.31 microM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Animais , Benzeno/química , Linhagem Celular , HIV/efeitos dos fármacos , HIV/enzimologia , HIV/fisiologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Naftiridinas/síntese química , Administração Oral , Animais , Células Cultivadas , Integrase de HIV/efeitos dos fármacos , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Mutação , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 5-amino derivatives of 8-hydroxy[1,6]-naphthyridine-7-carboxamide exhibiting sub-micromolar potency against replication of HIV-1 in cell culture was identified. One of these analogs, compound 12, displayed excellent pharmacokinetic properties when dosed orally in rats and in monkeys. This compound was demonstrated to be efficacious against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Naftiridinas/química , Naftiridinas/farmacologia , Aminação , Inibidores de Integrase de HIV/química , Estrutura Molecular , Naftiridinas/síntese química , Relação Estrutura-AtividadeRESUMO
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.