RESUMEN
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Neuralgia/tratamiento farmacológico , Oxadiazoles/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indoles/química , Indoles/farmacocinética , Ratones , Oxadiazoles/química , Oxadiazoles/farmacocinética , RatasRESUMEN
BACKGROUND: Septic arthritis of the knee joint requires prompt diagnosis and treatment for optimal outcomes. Pyomyositis with abscess formation is uncommon but may present with similar symptoms in the vicinity of a joint. OBJECTIVE: This report describes two cases of medial thigh abscess initially diagnosed and treated as septic arthritis, and highlights the need to make an accurate diagnosis. CASE REPORT: Two patients presenting with knee pain secondary to pyomyositis and abscess formation in the medial thigh were investigated with aspiration and treated subsequently with knee surgery, resulting in contamination of the knee joint in one case and delayed diagnosis with significant morbidity in both. CONCLUSION: Failure to identify a soft tissue infection may lead to delayed diagnosis, misdirected treatment, and contamination of a normal joint. Diagnosis is best confirmed with thorough physical examination and specific imaging where available.
Asunto(s)
Absceso/diagnóstico , Artritis Infecciosa/diagnóstico , Articulación de la Rodilla , Infecciones Estafilocócicas/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Muslo , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piomiositis/diagnósticoRESUMEN
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Receptor Cannabinoide CB1/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Compuestos Heterocíclicos/administración & dosificación , RatasRESUMEN
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Asunto(s)
Amidas/química , Indoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Perros , Evaluación Preclínica de Medicamentos , Indoles/síntesis química , Indoles/farmacocinética , Masculino , Ratones , Modelos Moleculares , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole (+)-24. (+)-24 was found to be a high affinity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic effects when administered iv to rodents.
Asunto(s)
Bencimidazoles/química , Modelos Moleculares , Receptores Opioides/agonistas , Analgésicos/química , Animales , Bencimidazoles/farmacología , Hipnóticos y Sedantes/química , Roedores , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A series benzylpiperidinium and benzylpyridinium quaternary salts have been synthesised and tested for inhibition of acetylcholinesterase and reversal of neuromuscular block induced by vecuronium. Several potent reversal agents have been identified and their haemodynamic effects measured.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Indanos/farmacología , Fármacos Neuromusculares no Despolarizantes/antagonistas & inhibidores , Piperidinas/farmacología , Bromuro de Vecuronio/antagonistas & inhibidores , Inhibidores de la Colinesterasa/química , Donepezilo , Indanos/química , Piperidinas/químicaRESUMEN
A series of piperidinium and pyridinium agents containing a common structural fragment of 5,6-dimethoxybenzothiophene have been synthesised as water-soluble acetylcholinesterase inhibitors. Several compounds, for example 42 (AChE IC(50) 0.03 microM) have been found to reverse the neuromuscular blockade induced by vecuronium bromide in vitro and in vivo. Coupled with their high water solubility (up to 30-60 mg/mL), these compounds are potentially useful as intravenous reversal agents of neuromuscular blocking agents in surgical anaesthesia.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Bromuro de Vecuronio/antagonistas & inhibidores , Animales , Inhibidores de la Colinesterasa/química , Cricetinae , Diafragma/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/química , Piperidinas/química , Piridinas/química , Solubilidad , AguaRESUMEN
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.