RESUMO
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
Assuntos
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidases/química , Invenções , Inibidores de Proteases/farmacologia , Amidas , Antivirais/farmacologia , Antivirais/químicaRESUMO
Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.
RESUMO
Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
Assuntos
Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Malária/tratamento farmacológico , Animais , Transmissão de Doença Infecciosa/prevenção & controle , Estágios do Ciclo de Vida/efeitos dos fármacos , Merozoítos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacosRESUMO
A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Piperidinas/química , Piperidinas/síntese química , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Amidas/química , Técnicas de Química Sintética , Lactamas/química , Fenol/químicaRESUMO
The tremendous therapeutic potential of voltage-gated sodium channels (Na(v)s) has been the subject of many studies in the past and is of intense interest today. Na(v)1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summarize the current status of research in the Na(v) field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Na(v) channel subtypes. We discuss Na(v) channel ligands such as small molecules, toxins isolated from animal venoms, and the recently identified Na(v)1.7-selective antibody. Furthermore, we review eight characterized ligand binding sites on the Na(v) channel α subunit. Finally, we examine possible therapeutic applications of Na(v) ligands and provide an update on current clinical studies.
Assuntos
Canais de Sódio Disparados por Voltagem/fisiologia , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Canalopatias/tratamento farmacológico , Canalopatias/genética , Ensaios Clínicos como Assunto , Indústria Farmacêutica , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Humanos , Ativação do Canal Iônico , Ligantes , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/genéticaRESUMO
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Assuntos
Inibidores de Integrase de HIV/química , Oxidiazóis/química , Pró-Fármacos/química , Pirimidinonas/química , Pirrolidinonas/química , Acetais/química , Animais , Área Sob a Curva , Carbonatos/química , Cães , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Hepatócitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Curva ROC , Raltegravir Potássico , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
Assuntos
Descoberta de Drogas , Receptor A2A de Adenosina/efeitos dos fármacos , Agonistas do Receptor A2 de Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Cristalografia por Raios X , Humanos , Ligantes , Conformação Proteica , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Transdução de SinaisRESUMO
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.