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
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Asunto(s)
Descubrimiento de Drogas , Compuestos Heterocíclicos con 2 Anillos/farmacología , Isoquinolinas/farmacología , Proteína Quinasa de Distrofia Miotónica/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 2 Anillos/química , Humanos , Isoquinolinas/química , Estructura Molecular , Proteína Quinasa de Distrofia Miotónica/metabolismo , Relación Estructura-ActividadRESUMEN
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50â¯=â¯43â¯nM; AhR activationâ¯=â¯2.3-fold).
Asunto(s)
Inductores del Citocromo P-450 CYP1A2/farmacología , Citocromo P-450 CYP1A2/biosíntesis , Descubrimiento de Drogas , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Regulación Alostérica/efectos de los fármacos , Animales , Antiparkinsonianos/farmacología , Inducción Enzimática/efectos de los fármacos , Humanos , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Organofosfatos/uso terapéutico , Piperidinas/uso terapéutico , Profármacos/uso terapéutico , Pirrolidinonas/uso terapéutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administración Intravenosa , Regulación Alostérica , Animales , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Ondas Encefálicas/efectos de los fármacos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Trastornos Disociativos/inducido químicamente , Macaca fascicularis , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Organofosfatos/efectos adversos , Organofosfatos/farmacocinética , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Profármacos/efectos adversos , Profármacos/farmacocinética , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Ensayo de Unión Radioligante , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , XenopusRESUMEN
A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.
Asunto(s)
Profármacos/síntesis química , Profármacos/farmacología , Pirazinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Profármacos/farmacocinética , Pirazinas/farmacocinética , RatasRESUMEN
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
Asunto(s)
Éteres/farmacología , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Triazoles/farmacología , Administración Oral , Regulación Alostérica/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Éteres/administración & dosificación , Éteres/química , Haplorrinos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/metabolismo , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/químicaRESUMEN
A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
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Carbamatos/farmacología , Pirazinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Carbamatos/síntesis química , Carbamatos/metabolismo , Línea Celular Tumoral , Humanos , Microsomas Hepáticos/metabolismo , Pirazinas/síntesis química , Pirazinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.
Asunto(s)
Convulsivantes/química , Oxazolidinonas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Convulsivantes/metabolismo , Convulsivantes/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacología , Ratas , Receptor del Glutamato Metabotropico 5/agonistas , Receptor del Glutamato Metabotropico 5/química , Reconocimiento en Psicología/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
Asunto(s)
Oxazolidinonas/farmacología , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Antagonistas del Receptor de Neuroquinina-1/química , Antagonistas del Receptor de Neuroquinina-1/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Antidepresivos/química , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Gerbillinae , Humanos , Antagonistas del Receptor de Neuroquinina-1/farmacocinética , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinéticaRESUMEN
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
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
RESUMEN
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
Asunto(s)
Química Farmacéutica , Poder Psicológico , Humanos , FemeninoRESUMEN
A series of pyrazinones were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients are discussed herein.
Asunto(s)
Tomografía de Emisión de Positrones , Pirazinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Encéfalo , Humanos , Estructura Molecular , Pirazinas/química , Ratas , Receptores de Hormona Liberadora de Corticotropina/químicaRESUMEN
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
Asunto(s)
Depresión/tratamiento farmacológico , Diseño de Fármacos , Antagonistas del Receptor de Neuroquinina-1 , Piridinas/síntesis química , Antagonistas de la Serotonina , Animales , Modelos Animales de Enfermedad , Gerbillinae , Concentración 50 Inhibidora , Estructura Molecular , Piridinas/química , Piridinas/uso terapéutico , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/uso terapéuticoRESUMEN
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Asunto(s)
Amidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Sulfonamidas/química , Amidas/síntesis química , Amidas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
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
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.
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Compuestos de Anilina/química , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Pirazinas/química , Pirazoles/química , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Flúor/sangre , Imagenología Tridimensional , Estructura Molecular , Pirazoles/metabolismo , Ratas , Distribución TisularRESUMEN
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.