RESUMEN
A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Asunto(s)
Aminas/farmacología , Hepatocitos/efectos de los fármacos , Norepinefrina/antagonistas & inhibidores , Éteres Fenílicos/farmacología , Piridinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT1 , Aminas/síntesis química , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Éteres Fenílicos/síntesis química , Piridinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Metilaminas/farmacología , Norepinefrina/antagonistas & inhibidores , Piridinas/farmacología , Inhibidores de Captación Adrenérgica/síntesis química , Animales , Transporte Biológico , Células CACO-2 , Inhibidores Enzimáticos del Citocromo P-450 , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Líquido Extracelular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Metilaminas/síntesis química , Microdiálisis , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Corteza Prefrontal/efectos de los fármacos , Piridinas/síntesis química , Ratas , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores del Citocromo P-450 CYP2D6 , Norepinefrina/antagonistas & inhibidores , Pirrolidinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Aminas/química , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Ligandos , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Modelos Químicos , Conformación Molecular , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
Asunto(s)
Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Neprilisina/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Animales , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Estructura Molecular , Inhibidores de Proteasas/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , PorcinosRESUMEN
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
Asunto(s)
Ácidos Carbocíclicos/síntesis química , Amidas/síntesis química , Neprilisina/antagonistas & inhibidores , Ácidos Pentanoicos/síntesis química , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Tiadiazoles/síntesis química , Ácidos Carbocíclicos/farmacocinética , Ácidos Carbocíclicos/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Células CHO , Clítoris/irrigación sanguínea , Clítoris/efectos de los fármacos , Cricetinae , Cricetulus , Perros , Femenino , Humanos , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Conejos , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/farmacología , Vagina/irrigación sanguínea , Vagina/efectos de los fármacosRESUMEN
A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.