RESUMO
The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies have shown that disrupting the assembly of the capsid can effectively combat the virus, and small molecule drugs that target the HBV capsid assembly modulator (CAM) process have been successful in clinical trials. Herein is described a distinct series of di-fluoro azepane CAMs with exceptional potency, pharmacokinetic, and solubility properties.
Assuntos
Capsídeo , Vírus da Hepatite B , Capsídeo/metabolismo , Montagem de Vírus , Antivirais/metabolismo , Proteínas do Capsídeo/metabolismo , Replicação ViralRESUMO
The HBV capsid core protein serves a number of important functions in the viral life cycle enabling chronic HBV infection to persist, and therefore is a promising drug target. Interfering with capsid assembly has shown efficacy in clinical trials with small molecule capsid assembly modulators (CAMs). Herein is described the further optimization of a progressive series of diazepinone HBV CAMs.
Assuntos
Capsídeo , Vírus da Hepatite B , Antivirais/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/metabolismo , Montagem de VírusRESUMO
Herein, a tandem approach that allows rapid access to the benzomorpholine scaffold is reported. This operationally simple method allows for valuable heterocycles to be isolated in moderate to high yields. The overall transformation consists of an initial C-N coupling, demonstrated using traditional Ullmann or Buchwald-Hartwig conditions, followed by an in situ oxetane ring opening. A range of functionality is tolerated on the aryl ring, and the cyclization exposes a pendant hydroxymethyl substituent, providing opportunities for further functionalization.
Assuntos
Aminação , Ciclização , Éteres CíclicosRESUMO
The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug target. Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
Assuntos
Antivirais/farmacologia , Azepinas/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Antivirais/química , Azepinas/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.
Assuntos
Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Antivirais/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Animais , Antineoplásicos/química , Compostos de Bifenilo/química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Di-Hidro-Orotato Desidrogenase , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Relação Estrutura-AtividadeRESUMO
NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC50) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 and 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achieved in mice and, thus, enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.
Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Capsídeo/efeitos dos fármacos , DNA Viral/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Piperidinas/farmacologia , RNA Viral/antagonistas & inibidores , Animais , Antígenos Virais/genética , Antígenos Virais/metabolismo , Antivirais/sangue , Antivirais/química , Antivirais/farmacocinética , Benzamidas/sangue , Benzamidas/química , Benzamidas/farmacocinética , Capsídeo/química , Capsídeo/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Hep G2 , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Piperidinas/sangue , Piperidinas/química , Piperidinas/farmacocinética , Cultura Primária de Células , RNA Viral/genética , RNA Viral/metabolismo , Proteínas do Core Viral/antagonistas & inibidores , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
The HBV core protein has multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly process has shown clinical efficacy in early clinical trials. Herein is described the SAR exploration of NVR 3-778, the first clinical compound in the sulfonyl carboxamide class.
Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Benzamidas/síntese química , Benzamidas/química , Proteínas do Capsídeo/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite B/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Montagem de Vírus/efeitos dos fármacosRESUMO
The current standard of care for treating Alzheimer's disease is acetylcholinesterase inhibitors, which nonselectively increase cholinergic signaling by indirectly enhancing activity of nicotinic and muscarinic receptors. These drugs improve cognitive function in patients, but also produce unwanted side effects that limit their efficacy. In an effort to selectively improve cognition and avoid the cholinergic side effects associated with the standard of care, various efforts have been aimed at developing selective M1 muscarinic receptor activators. In this work, we describe the preclinical and clinical pharmacodynamic effects of the M1 muscarinic receptor-positive allosteric modulator, MK-7622. MK-7622 attenuated the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine and altered quantitative electroencephalography (qEEG) in both rhesus macaque and human. For both scopolamine reversal and qEEG, the effective exposures were similar between species. However, across species the minimum effective exposures to attenuate the scopolamine impairment were lower than for qEEG. Additionally, there were differences in the spectral power changes produced by MK-7622 in rhesus versus human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in humans for a selective M1 muscarinic receptor-positive allosteric modulator.
Assuntos
Quinazolinas/farmacologia , Receptor Muscarínico M1/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Quinazolinas/farmacocinética , Pesquisa Translacional BiomédicaRESUMO
In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.
Assuntos
Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/antagonistas & inibidores , Animais , Eletroencefalografia , Eletromiografia , Estrutura Molecular , Antagonistas dos Receptores de Orexina/química , RatosRESUMO
Orexin signaling, known to modulate arousal and vigilance, is also involved in nociception as orexin neurons project to regions of the brain and spinal cord involved in pain processing, and the administration of orexin peptides can alter pain response in a wide range of preclinical models. Pharmacological treatment with the potent, selective and structurally distinct dual orexin receptor antagonists (ORAs) DORA-12 and DORA-2 significantly reduced pain responses during both phases I and II of the mouse formalin pain model and significantly reversed hyperalgesia in the rat complete Freund's adjuvant pain model, respectively. Significant antinociceptive effects of DORA-12 in the formalin model were also observed in orexin 1 receptor (OX1R) knockout mice, but not orexin 2 receptor (OX2R) or OX1R/OX2R double knockout mice. Mechanical hypersensitivity was significantly reduced with a series of structurally distinct, potent and highly selective ORAs (DORA-2, DORA-12 and DORA-22) in the rat spinal nerve ligation (SNL) injury model of neuropathic pain. Selective pharmacological targeting of OX2R with 2-SORA-7 also reduced pain responses in acute inflammatory (complete Freund's adjuvant) and neuropathic (SNL) rat pain models. Performance on the rotarod test of psychomotor performance and baseline thermal sensitivity were not affected in OX1R/OX2R knockout mice or ORA-treated mice, indicating that the observed pain-reducing effects were not due to sedation or motor deficits. These findings indicate that ORAs have pain-reducing effects across a number of acute and chronic neuropathic preclinical mouse and rat pain models. Further studies on the potential pain-relieving effects of orexin receptor antagonism are warranted.
Assuntos
Analgésicos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Animais , Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.
Assuntos
Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Animais , Descoberta de Drogas , Humanos , Piperidinas/farmacocinética , Ratos , Ratos Transgênicos , Relação Estrutura-AtividadeRESUMO
Improved treatment of Alzheimer disease (AD) is a significant unmet medical need that is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by gastrointestinal side effects owing to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA (1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4 H-quinolizine-3-carboxylic acid) has been demonstrated to improve cognition in a variety of rodent and nonhuman primate cognition models without producing significant gastrointestinal side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in nonhuman primates: paired-associates learning (PAL) and the continuous-performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of subeffective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1-positive allosteric modulators, either as monotherapy or as an add-on to current standards of care, have potential to reduce the cognitive deficits associated with AD.
Assuntos
Atenção/efeitos dos fármacos , Memória/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piperidinas/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Quinolizinas/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Animais , Aprendizagem por Associação/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Donepezila , Relação Dose-Resposta a Droga , Indanos/farmacologia , Macaca mulatta , Masculino , Antagonistas Muscarínicos/farmacologia , Escopolamina/farmacologiaRESUMO
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
Assuntos
Éteres/química , Antagonistas dos Receptores de Orexina , Piperidinas/química , Pirimidinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Éteres/síntese química , Éteres/farmacocinética , Meia-Vida , Humanos , Receptores de Orexina/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Sono/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Pirimidinas/síntese química , Pirimidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.
Assuntos
Antagonistas dos Receptores de Orexina/química , Receptores de Orexina/química , Piperidinas/química , Triazóis/química , Animais , Cães , Meia-Vida , Camundongos , Antagonistas dos Receptores de Orexina/farmacocinética , Antagonistas dos Receptores de Orexina/uso terapêutico , Receptores de Orexina/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ligação Proteica , Pirimidinas/química , Ratos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/veterinária , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/uso terapêuticoRESUMO
BACKGROUND: The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species. RESULTS: Active-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep. CONCLUSION: DORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.
Assuntos
Compostos Azabicíclicos/farmacologia , Azepinas/farmacologia , Benzimidazóis/farmacologia , Moduladores GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Sono/efeitos dos fármacos , Triazóis/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Estudos Cross-Over , Cães , Eletroencefalografia , Zopiclona , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Antagonistas dos Receptores de Orexina , Orexinas , Ratos Sprague-Dawley , Ratos Transgênicos , Sono/fisiologia , Privação do Sono/tratamento farmacológico , Privação do Sono/fisiopatologia , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Especificidade da Espécie , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.
Assuntos
Amidas/química , Naftalenos/química , Quinolizidinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Camundongos , Ligação Proteica , Receptor Muscarínico M1/química , Relação Estrutura-AtividadeRESUMO
Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.
Assuntos
Acetileno/química , Antagonistas dos Receptores de Orexina , Piperidinas/farmacologia , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Camundongos , Camundongos Knockout , Estrutura Molecular , Receptores de Orexina/deficiência , Receptores de Orexina/metabolismo , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.