RESUMEN
Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.
RESUMEN
Modulating GPR88 activity is suggested to have therapeutic utility in the treatment of CNS disorders, such as schizophrenia. This Letter will describe the discovery and SAR development of a class of potent GPR88 agonists.
Asunto(s)
Amidas/farmacología , Aminas/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Amidas/síntesis química , Amidas/química , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.
Asunto(s)
Aminas/farmacología , Diseño de Fármacos , Etanolaminas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Etanolaminas/síntesis química , Etanolaminas/química , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose systemic D-serine or glycine treatment. In this manuscript, we characterize Compound 1 (BMS-466442), the first known small molecule inhibitor of asc-1. Compound 1 selectively inhibited asc-1 mediated D-serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc-1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc-1 transporter and may provide a new path for the development of asc-1 inhibitors for the treatment of schizophrenia.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Agonistas de Aminoácidos Excitadores/farmacología , Histidina/análogos & derivados , Indoles/síntesis química , Indoles/farmacología , Receptores de N-Metil-D-Aspartato/agonistas , Aminoácidos/metabolismo , Animales , Línea Celular , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Glicina/metabolismo , Histidina/síntesis química , Histidina/farmacología , Humanos , Ratas , Ratas Sprague-Dawley , Serina/metabolismo , Bibliotecas de Moléculas Pequeñas , Sinaptosomas/metabolismoRESUMEN
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Asunto(s)
Pteridinas/química , Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Semivida , Pteridinas/síntesis química , Pteridinas/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
Asunto(s)
Neuralgia , Quinolinas , Amidas/farmacología , Amidas/uso terapéutico , Animales , Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound 58, a central pyridine isomer of BMS-986176/LX-9211 (4), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4.
Asunto(s)
Anestésicos Generales , Neuralgia , Animales , Éteres/uso terapéutico , Ratones , Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Médula Espinal , Relación Estructura-ActividadRESUMEN
Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of µ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.
Asunto(s)
Amidas/farmacología , Antiinflamatorios no Esteroideos/farmacología , Encéfalo/enzimología , Neuralgia/tratamiento farmacológico , Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Células CACO-2 , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neuralgia/metabolismo , Proteínas Quinasas/síntesis química , Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Asunto(s)
Modelos Moleculares , Pteridinas/síntesis química , Piridazinas/síntesis química , Relación Estructura-Actividad Cuantitativa , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Plexo Coroideo/metabolismo , Lóbulo Frontal/metabolismo , Técnicas In Vitro , Pteridinas/química , Pteridinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , PorcinosRESUMEN
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
Asunto(s)
Pirazinas/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Ansiolíticos/síntesis química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Unión Competitiva , Perros , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Semivida , Técnicas In Vitro , Masculino , Pirazinas/farmacocinética , Pirazinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
Potent cyclin dependent kinase inhibitors were prepared using parallel synthesis methodology. Treating advanced intermediate 2 with a variety of hydrazides in DMSO at 80 degrees C for 30 min gave the desired acylsemicarbazides in good to excellent yield. Several compounds were active against cdk4/D1 and cdk2/E in the low nanomolar range. The SAR indicates a wide variety of substituents are tolerated at the acylsemicarbazide moiety.