RESUMEN
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Asunto(s)
Piperazinas/síntesis química , Piridazinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/síntesis química , Animales , Perros , Diseño de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacocinética , Relación Estructura-Actividad , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológicoRESUMEN
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
Asunto(s)
Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/síntesis química , Diseño de Fármacos , Receptores de Dopamina D3/agonistas , Administración Intranasal , Animales , Cristalografía por Rayos X , Perros , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacocinética , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Receptores de Dopamina D3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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 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
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.