RESUMEN
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
RESUMEN
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Proteínas Protozoarias/metabolismo , Tetraoxanos/química , Tetraoxanos/farmacología , Animales , Antimaláricos/química , Perros , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/genética , Eritrocitos/parasitología , Femenino , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Plasmodium falciparum/genética , Plasmodium vivax/genética , Ratas , Ratas Sprague-Dawley , Tetraoxanos/farmacocinética , TransgenesRESUMEN
There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
Asunto(s)
Antimaláricos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Malaria/parasitología , Plasmodium/efectos de los fármacos , Plasmodium/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Descubrimiento de Drogas , Femenino , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/tratamiento farmacológico , Masculino , Modelos Moleculares , Factor 2 de Elongación Peptídica/antagonistas & inhibidores , Factor 2 de Elongación Peptídica/metabolismo , Plasmodium/genética , Plasmodium/crecimiento & desarrollo , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/metabolismo , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinéticaRESUMEN
AIMS: The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. METHODS: Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100-800 mg and 160-1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. RESULTS: A significant relation between plasma concentrations and placebo-corrected change from baseline QTc F (ΔΔQTc F) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml(-1) (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTc F effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml(-1) ) and 1440 mg (281 ng ml(-1) ), respectively, administered in the fasted state. CONCLUSIONS: Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.
Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Peróxidos/efectos adversos , Quinolinas/efectos adversos , Adamantano/administración & dosificación , Adamantano/efectos adversos , Adamantano/sangre , Adamantano/farmacocinética , Adolescente , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/sangre , Antimaláricos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Peróxidos/administración & dosificación , Peróxidos/sangre , Peróxidos/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/sangre , Quinolinas/farmacocinética , Adulto JovenRESUMEN
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Asunto(s)
Amidas/farmacología , Antimaláricos/farmacología , Bencimidazoles/farmacología , Eritrocitos/parasitología , Malaria/parasitología , Plasmodium falciparum/efectos de los fármacos , Pirazoles/farmacología , Sodio/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Femenino , Homeostasis/efectos de los fármacos , Humanos , Masculino , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/genética , Plasmodium berghei/metabolismo , Plasmodium falciparum/enzimología , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas ProtozoariasRESUMEN
Cardiovascular toxicity remains a major cause of concern during preclinical and clinical development as well as contributing to post-approval withdrawal of medicines. This issue is particularly relevant for anticancer drugs where, the significant improvement in the life expectancies of patients has dramatically extended the use and duration of drug therapies. Nevertheless, cardiotoxicity is also observed with other classes of drugs, including antibiotics, antidepressants, and antipsychotics. This article summarizes the clinical manifestations of drug-induced cardiotoxicity by various cancer chemotherapies and novel drugs for the treatment of other diseases. Furthermore, it presents on overview of biomarker and imaging techniques for the detection of drug-induced cardiotoxicity. Guidelines for the management of patients exposed to drugs with cardiotoxic potential are presented as well as a checklist for collecting information when a safety signal is observed in clinical trials to more effectively assess the risk of cardiotoxicity and manage patient safety.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Animales , Cardiotoxinas/efectos adversos , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , HumanosRESUMEN
The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3-diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.
Asunto(s)
Antimaláricos/farmacología , Quinolonas/farmacología , Animales , Antimaláricos/química , Atovacuona/química , Atovacuona/farmacología , Resistencia a Medicamentos , Sinergismo Farmacológico , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Ratones , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Proguanil/química , Proguanil/farmacología , Piridonas/química , Piridonas/farmacología , Quinolonas/químicaRESUMEN
In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.
Asunto(s)
Evaluación Preclínica de Medicamentos/tendencias , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Animales , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Medición de Riesgo/métodos , Sociedades Farmacéuticas , Pruebas de Toxicidad/tendenciasRESUMEN
A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.