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1.
Bioorg Med Chem Lett ; 97: 129541, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37952596

RESUMO

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.


Assuntos
Precursores Enzimáticos , Metaloproteinase 9 da Matriz , Metaloproteinase 9 da Matriz/metabolismo , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Indóis/farmacologia , Indóis/metabolismo , Metaloendopeptidases/metabolismo , Inibidores de Metaloproteinases de Matriz
2.
J Pharmacol Exp Ther ; 375(2): 276-285, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32862143

RESUMO

Histamine H3 receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H3 receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H3 receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H3 receptor agonist)-induced dipsogenia, and occupied the histamine H3 receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H3 receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H3 receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H3 receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H3 receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H3 receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.


Assuntos
Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Antagonistas dos Receptores Histamínicos/farmacocinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neurotransmissores/metabolismo , Ratos
3.
Bioorg Med Chem ; 28(13): 115489, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32482533

RESUMO

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (-)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (-)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9-2.0 h. Thus, (-)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia.


Assuntos
Antagonistas dos Receptores de Orexina/síntese química , Receptores de Orexina/metabolismo , Orexinas/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Masculino , Estrutura Molecular , Antagonistas dos Receptores de Orexina/farmacocinética , Orexinas/farmacocinética , Ratos Wistar , Sono/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 25(20): 5203-5215, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28807572

RESUMO

The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2.01nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2.


Assuntos
Benzamidas/farmacologia , Receptores de Orexina/metabolismo , Pirazóis/farmacologia , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
5.
Bioorg Med Chem ; 23(6): 1260-75, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25693785

RESUMO

Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2-1.4h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials.


Assuntos
Benzamidas/farmacologia , Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Triazóis/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/química , Células CHO , Cricetulus , Cães , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
7.
Chem Pharm Bull (Tokyo) ; 55(8): 1232-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17666851

RESUMO

In the present study, conducted to explore potent and small molecular melanocortin-4 (MC4) receptor ligands, we found that tripeptide 3a, containing a D-Phe-Arg-2-Nal (Nal; naphthylalanine) sequence, exhibited a moderate affinity for the MC4 receptor. Structural optimization led to the identification of a compound with a high affinity for the MC4 receptor, namely, tripeptide 3e, which showed a 70-fold higher affinity for the MC4 receptor than the lead compound 3a. Moreover, in an effort to further reduce the peptidic characters of tripeptide 3e, we found that dipeptide 3g exhibited a relatively high affinity for the MC4 receptor. Furthermore, in these analogues, the substituted position (1' vs. 2') of the naphthyl ring of Nal residue at position 7 was found to be important for the differentiation of agonist and antagonist activity. The synthesis and structure-activity relationships of the arginine analogues as MC4 receptor ligands were described in this paper.


Assuntos
Arginina/análogos & derivados , Arginina/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Células COS , Chlorocebus aethiops , AMP Cíclico/metabolismo , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Peso Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
8.
Chem Pharm Bull (Tokyo) ; 55(7): 1044-50, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17603198

RESUMO

While examining antagonists of the melanocortin-4 receptor (MC4 receptor), we found that compound 12b, containing a diphenylmethyl moiety, had a relatively high affinity for the MC4 receptor. When diphenylmethyl analogues were further examined, compounds 12c and 18 were also found to exhibit a high affinity for the MC4 receptor (IC(50)=46.7 nM and 33.2 nM, respectively). Furthermore, compound 12c was also found to show a high affinity for the serotonin transporter (IC(50)=10.7 nM). Here, we describe the synthesis and biological evaluation of various diphenylmethyl analogues in relation to their actions on the MC4 receptor and the serotonin transporter.


Assuntos
Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacologia , Receptor Tipo 4 de Melanocortina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Concentração Inibidora 50 , Estrutura Molecular , Receptor Tipo 4 de Melanocortina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 15(5): 1989-2005, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17234422

RESUMO

During the investigation of antagonists for the MC4 receptor, we found that 10ab having a naphthyl group showed almost the same binding affinity for the MC4 receptor as that of the lead compound 1 with a benzoyl group. We also developed a new type of compounds, namely, bis-piperazines, and found that the bis-piperazines 10 exhibited a high affinity for the MC4 receptor. In particular, (-)-10bg exhibited the highest affinity for the MC4 receptor with an IC50 value of 8.13nM. In this paper, we present the design, synthesis, and structure-activity relationships of the novel bis-piperazines as MC4 receptor antagonists.


Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Células COS , Chlorocebus aethiops , Espectroscopia de Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
10.
Bioorg Med Chem ; 15(6): 2375-85, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17267226

RESUMO

In the present study, we found that a novel piperazine compound, 11a, showed a moderate affinity (IC(50)=333nM) for the MC4 receptor. We developed the new type of piperazine compounds and found that mono-piperazine 11b exhibited a high-affinity (IC(50)=40.3nM) for the MC4 receptor. We also found that a series of biphenyl analogues exhibited a high-affinity for the receptor, and in particular, compound 11j exhibited the highest affinity for the MC4 receptor with an IC(50) value of 14.5nM. Furthermore, some of these compounds, when administered orally, significantly reversed the stress-induced anxiety-like behavior in rats. In this paper, we report the synthesis, structure-activity relationships, and oral activity of the novel mono-piperazines as MC4 receptor antagonists.


Assuntos
Ansiolíticos/farmacologia , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Comportamento Animal/efeitos dos fármacos , Células COS/efeitos dos fármacos , Chlorocebus aethiops , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-Atividade
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