RESUMEN
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lactamas/farmacología , Lactamas/uso terapéutico , Leucina/farmacología , Leucina/uso terapéutico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Prolina/farmacología , Prolina/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Inhibidores de Proteasa Viral/farmacología , Inhibidores de Proteasa Viral/uso terapéutico , Administración Oral , Animales , COVID-19/virología , Ensayos Clínicos Fase I como Asunto , Coronavirus/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Humanos , Lactamas/administración & dosificación , Lactamas/farmacocinética , Leucina/administración & dosificación , Leucina/farmacocinética , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Prolina/administración & dosificación , Prolina/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , SARS-CoV-2/fisiología , Inhibidores de Proteasa Viral/administración & dosificación , Inhibidores de Proteasa Viral/farmacocinética , Replicación Viral/efectos de los fármacosRESUMEN
To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.
Asunto(s)
Lactamas/síntesis química , Lactamas/farmacología , Prostaglandinas E Sintéticas/síntesis química , Prostaglandinas E Sintéticas/farmacología , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Administración Tópica , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Cricetinae , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Dinoprostona/química , Evaluación Preclínica de Medicamentos/métodos , Curación de Fractura/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Lactamas/administración & dosificación , Masculino , Ratones , Microesferas , Estructura Molecular , Poliglactina 910/administración & dosificación , Poliglactina 910/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazolidinas/químicaRESUMEN
Saurolactam and aristolactam BII, aristolactam-type alkaloids isolated from the aerial part of Saururus chinensis (Lour.) Ball (Saururaceae), showed significant neuroprotective activity against glutamate-induced toxicity in primary cultured rat cortical cells. The action mechanism of aristolactam BII, the more potent neuroprotective compound, was investigated using primary cultures of rat cortical cells as an in vitro system. Aristolactam BII attenuated glutamate-induced neurotoxicity significantly when it was added immediately or up to 9 h after the excitotoxic glutamate challenge. The alkaloid could not protect cultured neuronal cells from neurotoxicity induced by kainic acid or N-methyl- D-aspartate in a pre-treatment paradigm. However, aristolactam BII successfully reduced the overproduction of nitric oxide and the level of cellular peroxide in cultured neurons when it was treated as a post-treatment paradigm. These results may suggest that aristolactam BII exerts its significant neuroprotective effects on glutamate-injured primary cultures of rat cortical cells by directly inhibiting the production of nitric oxide.
Asunto(s)
Lactamas/farmacología , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/prevención & control , Óxido Nítrico/biosíntesis , Fitoterapia , Extractos Vegetales/farmacología , Saururaceae , Animales , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ácido Glutámico , Lactamas/administración & dosificación , Lactamas/uso terapéutico , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/etiología , Componentes Aéreos de las Plantas , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
We isolated five bacterial strains from patients diagnosed as having nocardiosis. Bacterial species were identified based on the similarities in the nucleotide sequences of 16S ribosomal RNAs. Three of the five strains were identified as Nocardia asteroids, but unexpectedly other two were Streptomyces hygroscopicus and Rothia dentocariosa. The latter two species are not members of the family Nocardiaceae. We investigated the susceptibilities of these five strains to the following nine antimicrobial agents: trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), erythromycin (EM), amikacin (AMK), cefotaxime (CTX), faropenem (FRPM), imipenem (IPM), ciprofloxacin (CPFX), and sparfloxacin (SPFX). The minimum inhibitory concentration (MIC) ranges (mg/ml) were as follows: TMP-SMX, 4- > 32; MINO, 0.125-8; EM, < or = 0.016- > 32; AMK, 1-2; CTX, 0.063- > 32; FRPM, 0.063-16; IPM, 0.125-2; CPFX, 4-32; and SPFX, 0.5-16. Moreover, the synergistic effects of AMK in combination with each of TMP-SMX, MINO, EM, CTX, IPM, and SPFX were investigated by checkerboard synergy testing. No antagonism was recognized for the three N. asteroides strains. Synergistic and additive effects were observed for the combinations of AMK with CTX, IPM, or SPFX.