RESUMEN
The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical µ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in ß-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased µ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased µ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos/farmacología , Descubrimiento de Drogas/métodos , Receptores Opioides mu/agonistas , Compuestos de Espiro/farmacología , Tiofenos/farmacología , Dolor Agudo/patología , Analgésicos/síntesis química , Analgésicos/química , Animales , Modelos Animales de Enfermedad , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Ratones , Modelos Químicos , Estructura Molecular , Ratas , Receptores Opioides mu/metabolismo , Índice de Severidad de la Enfermedad , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in ß-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the µ-opioid receptor (MOR) to G proteins, but not ß-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less ß-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
Asunto(s)
Analgésicos/farmacología , Proteínas de Unión al GTP/metabolismo , Tracto Gastrointestinal/efectos de los fármacos , Morfina/farmacología , Receptores Opioides mu/metabolismo , Sistema Respiratorio/efectos de los fármacos , Animales , Arrestinas/metabolismo , Línea Celular , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/metabolismo , Células HEK293 , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Enfermedades Respiratorias/inducido químicamente , Enfermedades Respiratorias/tratamiento farmacológico , Enfermedades Respiratorias/metabolismo , Transducción de Señal/efectos de los fármacos , Arrestina beta 2 , beta-ArrestinasRESUMEN
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Asunto(s)
Química Farmacéutica/métodos , Urotensinas/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Diaminas/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Receptores Opioides kappa/química , Estereoisomerismo , Relación Estructura-Actividad , Urotensinas/químicaRESUMEN
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Asunto(s)
Compuestos de Anilina/farmacología , Piperidonas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Oral , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Animales , Disponibilidad Biológica , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Peso Molecular , Piperidonas/síntesis química , Piperidonas/química , Ratas , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Fenilbutiratos/farmacología , Fenilbutiratos/farmacocinética , Acetatos/química , Administración Oral , Aminopiridinas/química , Animales , Disponibilidad Biológica , Adhesión Celular/efectos de los fármacos , Línea Celular , Semivida , Humanos , Fenilbutiratos/química , RatasRESUMEN
Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
Asunto(s)
Antibacterianos , Inhibidores Enzimáticos , Oxidorreductasas/antagonistas & inhibidores , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Enoil-ACP Reductasa (NADH) , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimología , Relación Estructura-ActividadRESUMEN
Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.