RESUMO
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.
Assuntos
Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/química , Amidas/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Isoxazóis/síntese química , Isoxazóis/uso terapêutico , Dor/tratamento farmacológico , Ratos , Canais de Cátion TRPV/metabolismoRESUMO
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.
Assuntos
Compostos Heterocíclicos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , RatosRESUMO
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.
Assuntos
Amidas/química , Anti-Hipertensivos/química , Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Hipertermia Induzida , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
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.
Assuntos
Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Capsaicina/toxicidade , Cicloexanóis/farmacocinética , Cicloexanóis/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
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.
Assuntos
Benzimidazóis/química , Antagonistas de Entorpecentes/química , Piperidinas/química , Animais , Cricetinae , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
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.
Assuntos
Androstanóis/química , Ciclodextrinas/síntese química , Fármacos Neuromusculares não Despolarizantes/síntese química , gama-Ciclodextrinas , Animais , Cristalografia por Raios X , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/inervação , Avaliação Pré-Clínica de Medicamentos , Cobaias , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Fármacos Neuromusculares não Despolarizantes/química , Rocurônio , Eletricidade Estática , Relação Estrutura-Atividade , SugammadexAssuntos
Androstanóis/química , Ciclodextrinas/química , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes/química , gama-Ciclodextrinas , Androstanóis/farmacologia , Animais , Cristalografia por Raios X , Ciclodextrinas/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/inervação , Técnicas In Vitro , Macaca mulatta , Camundongos , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rocurônio , SugammadexRESUMO
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.
Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Hipnóticos e Sedativos/síntese química , Receptores Opioides/agonistas , Animais , Roedores , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
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.