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1.
Bioorg Med Chem Lett ; 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503632

RESUMO

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).

2.
Bioorg Med Chem Lett ; 28(15): 2641-2646, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29958762

RESUMO

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 EC50 = 43 nM; AhR activation = 2.3-fold).

3.
ACS Med Chem Lett ; 9(5): 472-477, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795762

RESUMO

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

4.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28954811

RESUMO

(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.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Organofosfatos/uso terapêutico , Piperidinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Pirrolidinonas/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Intravenosa , Regulação Alostérica , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ondas Encefálicas/efeitos dos fármacos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Transtornos Dissociativos/induzido quimicamente , Macaca fascicularis , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Xenopus
5.
Bioorg Med Chem ; 25(20): 5490-5505, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28818462

RESUMO

Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.


Assuntos
Descoberta de Drogas , Modelos Biológicos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Neurônios/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química
6.
Neuropharmacology ; 118: 167-174, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28315351

RESUMO

Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the µ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 µM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Traumatismos da Medula Espinal/complicações , Aminas/farmacocinética , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ácidos Cicloexanocarboxílicos/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Lateralidade Funcional , Gabapentina , Haplorrinos , Hiperalgesia/etiologia , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Knockout , Naftiridinas/química , Naftiridinas/farmacocinética , Neuralgia/etiologia , Neuralgia/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteínas Serina-Treonina Quinases/genética , Ensaio Radioligante , Ratos , Trítio/farmacocinética , Ácido gama-Aminobutírico/farmacocinética
7.
Bioorg Med Chem Lett ; 27(6): 1360-1363, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28223020

RESUMO

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.


Assuntos
Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Disponibilidade Biológica , Pró-Fármacos/farmacocinética , Pirazinas/farmacocinética , Ratos
8.
Bioorg Med Chem ; 25(2): 496-513, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27914948

RESUMO

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.


Assuntos
Éteres/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Triazóis/farmacologia , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éteres/administração & dosagem , Éteres/química , Haplorrinos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/metabolismo , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
9.
ACS Med Chem Lett ; 7(12): 1082-1086, 2016 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-27994742

RESUMO

The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.

10.
Bioorg Med Chem Lett ; 26(24): 5871-5876, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27856084

RESUMO

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.


Assuntos
Oxazolidinonas/farmacologia , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/química , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade
11.
ACS Chem Neurosci ; 7(12): 1635-1640, 2016 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-27744678

RESUMO

Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.


Assuntos
Antidepressivos/farmacologia , Indazóis/farmacologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Administração Oral , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/toxicidade , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Gerbillinae , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/toxicidade , Camundongos , Estrutura Molecular , Antagonistas do Receptor de Neuroquinina-1/síntese química , Antagonistas do Receptor de Neuroquinina-1/química , Antagonistas do Receptor de Neuroquinina-1/toxicidade , Ratos , Receptores da Neurocinina-1/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/síntese química , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/toxicidade , Relação Estrutura-Atividade , Regulador Transcricional ERG/metabolismo
12.
Bioorg Med Chem Lett ; 26(17): 4165-9, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27496211

RESUMO

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.


Assuntos
Convulsivantes/química , Oxazolidinonas/química , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Convulsivantes/metabolismo , Convulsivantes/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5/agonistas , Receptor de Glutamato Metabotrópico 5/química , Recognição (Psicologia)/efeitos dos fármacos , Relação Estrutura-Atividade
13.
J Pharmacol Exp Ther ; 358(3): 371-86, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27411717

RESUMO

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.


Assuntos
Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/fisiopatologia
14.
ACS Chem Neurosci ; 7(9): 1192-200, 2016 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-27075300

RESUMO

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.


Assuntos
Fármacos atuantes sobre Aminoácidos Excitatórios/síntese química , Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia , Ácidos Picolínicos/farmacologia , Pirazóis/síntese química , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Fármacos atuantes sobre Aminoácidos Excitatórios/química , Humanos , Ácidos Picolínicos/química , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 26(9): 2184-7, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27020524

RESUMO

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.


Assuntos
Carbamatos/farmacologia , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/metabolismo , Linhagem Celular Tumoral , Humanos , Microssomos Hepáticos/metabolismo , Pirazinas/síntese química , Pirazinas/metabolismo , Ratos , Relação Estrutura-Atividade
16.
ACS Med Chem Lett ; 7(3): 289-93, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985317

RESUMO

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

17.
Neuropharmacology ; 102: 121-35, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26522433

RESUMO

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Sítios de Ligação , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo
18.
J Pharmacol Exp Ther ; 354(3): 340-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26109678

RESUMO

The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Animais , Células CHO , Linhagem Celular , Células Cultivadas , Cricetulus , Células HEK293 , Humanos , Camundongos , Ratos , Esquizofrenia/tratamento farmacológico
19.
Bioorg Med Chem Lett ; 25(15): 3039-43, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26048800

RESUMO

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.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Antagonistas do Receptor de Neuroquinina-1/química , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/química , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Compostos de Bifenilo/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Gerbillinae , Humanos , Antagonistas do Receptor de Neuroquinina-1/farmacocinética , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética
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