RESUMEN
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
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Asunto(s)
Anemia/tratamiento farmacológico , Compuestos Aza/síntesis química , Hidantoínas/síntesis química , Factor 1 Inducible por Hipoxia/metabolismo , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Animales , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Perros , Canal de Potasio ERG1 , Eritropoyetina/biosíntesis , Canales de Potasio Éter-A-Go-Go/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hidantoínas/farmacocinética , Hidantoínas/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Hígado/efectos de los fármacos , Hígado/enzimología , Macaca mulatta , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Regulación hacia ArribaRESUMEN
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Benzodiazepinonas/farmacología , Epilepsia/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Electrofisiología , Electrochoque , Epilepsia/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Asunto(s)
Amidas/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/síntesis química , Pirazinas/síntesis química , Triazoles/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Perros , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacología , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
Asunto(s)
Antiprotozoarios/síntesis química , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Eimeria tenella/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Piridinas/síntesis química , Alimentación Animal , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacología , Pollos , Coccidiosis/tratamiento farmacológico , Eimeria tenella/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Imidazoles/química , Imidazoles/farmacología , Masculino , Estructura Molecular , Pruebas de Mutagenicidad , Oocistos/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Asunto(s)
Ciclopentanos/química , Ciclopentanos/farmacología , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Animales , Ciclopentanos/síntesis química , Ciclopentanos/farmacocinética , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacocinética , Relación Estructura-ActividadRESUMEN
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Pirazinas/química , Pirazinas/farmacología , Triazoles/química , Triazoles/farmacología , Administración Oral , Animales , Sitios de Unión , Bioquímica/métodos , Glucemia/análisis , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Glucagón/sangre , Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/efectos de los fármacos , Conformación Proteica , Precursores de Proteínas/sangre , Precursores de Proteínas/efectos de los fármacos , Pirazinas/farmacocinética , Ratas , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacocinéticaRESUMEN
Syntheses and structure-activity relationships of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists are described. Some of substituents on the piperidine ring that were investigated included a fused phenyl group, a (6R)-trifluoromethyl group, (6S) and (6R)-methyl group. This study showed that GnRH binding potency was tolerated by a small group at the 6-position of the piperidine, and blocking the 6-position by a trifluoromethyl group reduced clearance rate and increased oral bioavailability.
Asunto(s)
Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Piperidinas/síntesis química , Quinolonas/síntesis química , Animales , Células CHO , Cricetinae , Perros , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Piperidinas/metabolismo , Unión Proteica/fisiología , Quinolonas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.