RESUMEN
The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
Asunto(s)
Cognición/efectos de los fármacos , Fenoles/farmacología , Trastornos Psicóticos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Anfetamina/antagonistas & inhibidores , Anfetamina/farmacología , Animales , Animales no Consanguíneos , Modelos Animales de Enfermedad , Fluorobencenos/farmacología , Fluorobencenos/uso terapéutico , Locomoción/efectos de los fármacos , Masculino , Fenciclidina/antagonistas & inhibidores , Fenciclidina/farmacología , Fenoles/farmacocinética , Fenoles/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/uso terapéutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Área Bajo la Curva , Encéfalo/metabolismo , Células CHO , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Indicadores y Reactivos , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Benzoatos/química , Células CHO , Cricetinae , Cricetulus , Inflamación/inducido químicamente , Inflamación/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Asunto(s)
Alprostadil/metabolismo , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Adyuvante de Freund , Semivida , Inflamación/inducido químicamente , Inflamación/complicaciones , Dolor/etiología , RatasRESUMEN
This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica , Encéfalo/metabolismo , Animales , Diálisis , Perros , Masculino , Ratones , Permeabilidad , Ratas , Solubilidad , Especificidad de la EspecieRESUMEN
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
Asunto(s)
Analgésicos/farmacología , Benzoatos/farmacología , Pirroles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Benzoatos/síntesis química , Disponibilidad Biológica , Ciclohexanos/química , Ciclopentanos/química , Inflamación/tratamiento farmacológico , Inflamación/patología , Ligandos , Dolor/tratamiento farmacológico , Dolor/patología , Pirroles/química , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
Asunto(s)
Benzoxazinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Benzoxazinas/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Estabilidad de Medicamentos , Humanos , Ensayo de Unión Radioligante , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfolipasas A/antagonistas & inhibidores , Pirimidinonas/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Cinética , Fosfolipasas A/sangre , Fosfolipasas A2 , Pirimidinonas/química , Conejos , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.