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1.
ACS Med Chem Lett ; 14(5): 645-651, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37197453

RESUMO

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

2.
Bioorg Med Chem Lett ; 73: 128904, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35868496

RESUMO

Chronic hepatitis B (CHB) is a major worldwide public health problem and novel anti-HBV therapies preventing liver disease progression to cirrhosis and hepatocellular carcinoma are urgently needed. Over the last several years, capsid assembly modulators (CAM) have emerged as clinically effective anti-HBV agents which can inhibit HBV replication in CHB patients. As part of a drug discovery program aimed at obtaining novel CAM endowed with high in vitro and in vivo antiviral activity, we identified a novel series of sulfamoylbenzamide (SBA) derivatives. Compound 10, one of the most in vitro potent SBA-derived CAM discovered to date, showed excellent pharmacokinetics in mice suitable for oral dosing. When studied in a transgenic mouse model of hepatic HBV replication, it was considerably more potent than NVR 3-778, the first sulfamoylbenzamide (SBA) CAM that entered clinical trials for CHB, at reducing viral replication in a dose-dependent fashion. We present herein the discovery process, the SAR analysis and the pre-clinical profile of this novel SBA CAM.


Assuntos
Antivirais , Capsídeo , Animais , Antivirais/farmacocinética , Proteínas do Capsídeo , Vírus da Hepatite B , Camundongos , Montagem de Vírus , Replicação Viral
3.
Bioorg Med Chem Lett ; 72: 128858, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35718104

RESUMO

A new series of in vitro potent and highly selective histone methyl transferase enzyme G9a inhibitors was obtained. In particular, compound 2a, one the most potent G9a inhibitor identified, was endowed with >130-fold selectivity over GLP and excellent ligand efficiency. Therefore, it may represent a valuable tool compound to validate the role of highly selective G9a inhibitors in different pathological conditions. When 2a was characterized in vitro in cellular models of skeletal muscle differentiation, a relevant increase of myofibers' size and reduction of the fibroadipogenic infiltration were observed, further confirming the therapeutic potential of selective G9a inhibitors for the treatment of Duchenne muscle dystrophy.


Assuntos
Histona-Lisina N-Metiltransferase , Histonas , Inibidores Enzimáticos/farmacologia
4.
Sci Adv ; 7(23)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34078594

RESUMO

H3K9 methylation maintains cell identity orchestrating stable silencing and anchoring of alternate fate genes within the heterochromatic compartment underneath the nuclear lamina (NL). However, how cell type-specific genomic regions are specifically targeted to the NL is still elusive. Using fibro-adipogenic progenitors (FAPs) as a model, we identified Prdm16 as a nuclear envelope protein that anchors H3K9-methylated chromatin in a cell-specific manner. We show that Prdm16 mediates FAP developmental capacities by orchestrating lamina-associated domain organization and heterochromatin sequestration at the nuclear periphery. We found that Prdm16 localizes at the NL where it cooperates with the H3K9 methyltransferases G9a/GLP to mediate tethering and silencing of myogenic genes, thus repressing an alternative myogenic fate in FAPs. Genetic and pharmacological disruption of this repressive pathway confers to FAP myogenic competence, preventing fibro-adipogenic degeneration of dystrophic muscles. In summary, we reveal a druggable mechanism of heterochromatin perinuclear sequestration exploitable to reprogram FAPs in vivo.

5.
ACS Med Chem Lett ; 10(4): 627-632, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30996808

RESUMO

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies.

6.
ChemMedChem ; 12(23): 1917-1926, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29117473

RESUMO

Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as an inhibitor of histone deacetylases (HDACs) and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported, allowing the identification of important structure-activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profiles, anticancer activity, and pharmacokinetic properties. The aim of this review is to concisely summarize the information obtained by biological evaluations of the various largazole analogues reported to date, with particular attention given to the latest analogues, as well as to analyze the various SAR obtained from this data, with the purpose of providing useful guidelines for the development of novel potent and selective HDAC inhibitors to be used as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Depsipeptídeos/síntese química , Depsipeptídeos/química , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Conformação Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
7.
Org Lett ; 17(3): 398-401, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25629303

RESUMO

The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.


Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Isoquinolinas/síntese química , Pirazinas/química , Pirazinas/síntese química , Aminoácidos/química , Catálise , Ciclização , Compostos Heterocíclicos com 3 Anéis/química , Isoquinolinas/química , Estrutura Molecular , Estereoisomerismo
8.
Bioorg Med Chem ; 21(21): 6264-73, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24075145

RESUMO

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.


Assuntos
Antidepressivos/química , Antagonistas dos Receptores de Neurocinina-1/química , Receptores da Neurocinina-1/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Células CHO , Cricetinae , Cricetulus , Cães , Feminino , Gerbillinae , Meia-Vida , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Ligação Proteica , Ratos , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo
9.
Eur J Pharmacol ; 692(1-3): 1-9, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-22796453

RESUMO

In this work the pharmacology and the receptor kinetics of the following orexin receptor antagonists SB-649868, ACT-078573, JNJ-10397049, MK-6096 and Roche-Cp were evaluated at human OX(1) and OX(2) orexin receptors by using functional and receptor binding assays. Kinetic analysis of the unlabeled ligands was carried out by indirect measurement according to the Motulski and Mahan's method as opposed to the direct measure by using labeled test compounds. All compounds antagonized orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK(B) values: SB-649868 (OX(1)=9.67; OX(2)=9.64), ACT-078573 (OX(1)=8.44; OX(2)=9.02), JNJ-10397049 (OX(1)=5.97; OX(2)=8.35), MK-6096 (OX(1)=9.13; OX(2)=9.79) and Roche-Cp (OX(1)=7.18; OX(2)=8.83). They displaced the [(3)H]ACT-078573 receptor binding with the following pK(i) values: SB-649868 (OX(1)=9.27; OX(2)=8.91), ACT-078573 (OX(1)=7.80; OX(2)=9.12), JNJ-10397049 (OX(1)=5.18; OX(2)=8.10), MK-6096 (OX(1)=8.39; OX(2)=8.90) and Roche-Cp (OX(1)=6.65; OX(2)=8.54). From dissociation kinetic studies using [(3)H]ACT-078573, the calculated long half-life, (t(½)) supported the non-surmountability profile of SB-649868 (t(½)=35.91min) at OX(1) orexin receptor. Similarly, the long or moderately long t(½) values for ACT-078573 at OX(2) orexin receptor (t(½)=69.71min), MK-6096 (t(½)=17.70min), SB-649868 (t(½)=8.09min) and Roche-Cp (t(½)=5.79min) sustained their non-surmountable profile. JNJ-10397049 showed short t(½) values at both receptor subtypes (OX(1)t(½)=0.19min; OX(2)t(½)=0.60min) with surmountable antagonism.


Assuntos
Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/metabolismo , Acetamidas/metabolismo , Acetamidas/farmacologia , Animais , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Dioxanos/metabolismo , Dioxanos/farmacologia , Humanos , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Cinética , Receptores de Orexina , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Tiazóis/metabolismo , Tiazóis/farmacologia
10.
Neuropsychopharmacology ; 37(9): 1999-2011, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22569505

RESUMO

Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine), a selective OX(1)R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N'-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX(2)R antagonist, and SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX(1)/OX(2)R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX(1)R mechanisms in BE, suggesting that selective antagonism at OX(1)R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.


Assuntos
Bulimia/metabolismo , Comportamento Compulsivo , Ingestão de Alimentos/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores de Neuropeptídeos/fisiologia , Animais , Bulimia/tratamento farmacológico , Bulimia/psicologia , Comportamento Compulsivo/tratamento farmacológico , Comportamento Compulsivo/psicologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/psicologia , Feminino , Frutose/análogos & derivados , Frutose/farmacologia , Frutose/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Masculino , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Esquema de Reforço , Fatores Sexuais , Topiramato , Células Tumorais Cultivadas
12.
Bioorg Med Chem Lett ; 21(18): 5562-7, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21831639

RESUMO

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.


Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Orexina , Piperidinas/síntese química , Piperidinas/química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
13.
Bioorg Med Chem ; 19(11): 3451-61, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21550808

RESUMO

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.


Assuntos
Inibidores da Captação Adrenérgica/química , Inibidores da Captação de Dopamina/química , Heptanos/química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/farmacologia , Heptanos/síntese química , Heptanos/farmacologia , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade
14.
J Med Chem ; 54(4): 1071-9, 2011 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-21229983

RESUMO

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/síntese química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Transtorno Depressivo/metabolismo , Descoberta de Drogas , Gerbillinae , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Piperazinas/química , Piperazinas/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Análise de Regressão , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Estereoisomerismo
15.
Bioorg Med Chem Lett ; 21(1): 602-5, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21134748

RESUMO

Two complementary stereospecific synthetic approaches for the preparation of unsymmetrical ortho-substituted N-(4,4-diphenylbut-3-enyl) derivatives of nipecotic acid are described. Determination of the activity of the prepared compounds at the GAT-1 transporter highlighted differing SAR requirements of the E- and Z-phenyl rings, and led to the discovery of a compound with comparable potency to tiagabine. Some attempts to replace nipecotic acid with alternative novel amino acids are also described.


Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Ácidos Nipecóticos/síntese química , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/farmacologia , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 20(24): 7259-64, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21074436

RESUMO

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.


Assuntos
Compostos Azabicíclicos/química , Oxidiazóis/química , Pirazóis/química , Piridinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Ligação Proteica , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
17.
J Med Chem ; 53(23): 8228-40, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21053897

RESUMO

In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.


Assuntos
Imidazóis/farmacologia , Quinolinas/farmacologia , Antagonistas da Serotonina/farmacologia , Administração Oral , Animais , Células CHO , Cromatografia Líquida , Cricetulus , Descoberta de Drogas , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Espectroscopia de Ressonância Magnética , Masculino , Quinolinas/administração & dosagem , Quinolinas/química , Ratos Sprague-Dawley , Receptores de Serotonina/classificação , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Espectrometria de Massas em Tandem
18.
Bioorg Med Chem Lett ; 20(24): 7308-11, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21055936

RESUMO

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.


Assuntos
Compostos Azabicíclicos/química , Imidazóis/química , Neuropeptídeos/antagonistas & inibidores , Piperidinas/química , Animais , Simulação por Computador , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Microssomos Hepáticos/metabolismo , Neuropeptídeos/metabolismo , Ratos , Termodinâmica
19.
Bioorg Med Chem Lett ; 20(23): 7120-3, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20951033

RESUMO

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Ratos , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 20(23): 7092-6, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20951584

RESUMO

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.


Assuntos
Quinolonas/química , Receptores 5-HT1 de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Animais , Autorreceptores/antagonistas & inibidores , Autorreceptores/efeitos dos fármacos , Quinolonas/farmacocinética , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sinapses/química
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