RESUMEN
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Asunto(s)
Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Capsaicina/toxicidad , Ciclohexanoles/farmacocinética , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.
Asunto(s)
Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , Isoxazoles/síntesis química , Isoxazoles/uso terapéutico , Dolor/tratamiento farmacológico , Ratas , Canales Catiónicos TRPV/metabolismoRESUMEN
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
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Asunto(s)
Amidas/química , Antihipertensivos/química , Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacocinética , Hipertermia Inducida , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.
Asunto(s)
Bencimidazoles/química , Antagonistas de Narcóticos/química , Piperidinas/química , Animales , Cricetinae , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Hipnóticos y Sedantes/síntesis química , Receptores Opioides/agonistas , Animales , Roedores , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores Opioides/agonistas , Animales , Células CHO , Cricetinae , AMP Cíclico/biosíntesis , Diseño de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Masculino , Ratones , Relación Estructura-Actividad , Transfección , Conducto Deferente , Receptor de NociceptinaAsunto(s)
Androstanoles/química , Ciclodextrinas/química , Bloqueo Neuromuscular , Fármacos Neuromusculares no Despolarizantes/química , gamma-Ciclodextrinas , Androstanoles/farmacología , Animales , Cristalografía por Rayos X , Ciclodextrinas/farmacología , Diafragma/efectos de los fármacos , Diafragma/inervación , Técnicas In Vitro , Macaca mulatta , Ratones , Modelos Moleculares , Contracción Muscular/efectos de los fármacos , Fármacos Neuromusculares no Despolarizantes/farmacología , Rocuronio , SugammadexRESUMEN
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.