RESUMO
The melanin-concentrating hormone-1 receptor (MCH1R) is a G-protein-coupled receptor expressed in the brain and peripheral tissues that regulates energy storage and body weight. Here, we focused on discovery of the mechanism and site of action for a small-molecule MCH1R antagonist, which yields weight loss in a mouse model of human obesity. MCH1R is expressed throughout the brain but also found in peripheral tissues known to regulate fat storage and utilization, e.g., skeletal muscle and adipose tissue. Previous studies of MCH1R antagonist studies have not delineated the site that is critical for mediating the anorexigenic and weight-reducing actions. In this study, we evaluated the role of the brain and peripheral tissue receptors. We developed a novel nonbrain-permeable MCH antagonist analog with a carboxylic acid moiety to specifically test the site of action. Based on in vitro and in vivo assays, the analog is not able to cross the blood-brain barrier and does not lead to inhibition of food intake and reduced body weight. The data clearly demonstrate that MCH1R antagonists need access to the brain to reduce body weight and fat mass. The brain-permeable MCH1R antagonist leads to significant reduction in body weight and fat mass in diet-induced obese mice. The effect is dose-dependent and appears to be partially driven by a reduction in food intake. Finally, these studies show the utility of a medicinal chemistry approach to address an important biological and pharmacological question.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Encéfalo/metabolismo , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/metabolismo , Fármacos Antiobesidade/farmacocinética , Aprendizagem da Esquiva , Peso Corporal/efeitos dos fármacos , Células CACO-2 , Linhagem Celular , Gorduras na Dieta/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-Evans , Receptores de Somatostatina/metabolismo , PaladarRESUMO
Despite the high number of drug-discovery programs dedicated to finding small-molecule MCH-R1 antagonists for the treatment of obesity and/or mood disorders, a very limited number of these have progressed into the clinic. Beyond the common challenges in drug design related to ADME and safety profiles, cardiovascular risk involving hERG binding and the potential for subsequent drug-induced QTc prolongation has been a major hurdle for a significant number of MCH-R1 research programs. Many of these programs have evolved, and effectively designed MCH antagonists having decreased hERG-binding affinity have emerged. Currently, however, only a selected few candidates have progressed to clinical development. Drug-design strategies, in vivo efficacy, ADME, and cardiovascular safety profiles for a selection of MCH-R1 antagonist research programs are discussed ahead.
Assuntos
Desenho de Fármacos , Transtornos do Humor/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Humanos , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R,4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S,4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.
Assuntos
Dipeptídeos/química , Prolina/análogos & derivados , Prolina/síntese química , Pirrolidinas/síntese química , Receptores de Melanocortina/agonistas , Ligação Competitiva , Linhagem Celular , Humanos , Ligantes , Conformação Molecular , Mimetismo Molecular , Prolina/farmacologia , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
Assuntos
Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Fármacos Antiobesidade/química , Disponibilidade Biológica , Dieta , Modelos Animais de Doenças , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Conformação Molecular , Piperazinas/química , Ratos , EstereoisomerismoRESUMO
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.
Assuntos
Compostos de Bifenilo/farmacologia , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Naftalenos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Compostos de Bifenilo/síntese química , Canal de Potássio ERG1 , Ergolinas/farmacologia , Humanos , Indicadores e Reagentes , Mianserina/farmacologia , Naftalenos/síntese química , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and biological testing of novel classes of potent melanin-concentrating hormone (MCH-R1) antagonists based on pyrazolopiperazinone and pyrrolopiperazinone scaffolds are described.
Assuntos
Piperazinas/síntese química , Pirazóis/síntese química , Pirróis/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Células CACO-2 , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Piperazinas/farmacologia , Pirazóis/farmacologia , Pirróis/farmacologia , Ensaio Radioligante , Receptor 5-HT2C de Serotonina/efeitos dos fármacosRESUMO
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM.
Assuntos
Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Naftalenos/farmacologia , Piperazinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Cães , Canal de Potássio ERG1 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Camundongos , Naftalenos/síntese química , Piperazinas/síntese química , Redução de Peso/efeitos dos fármacosRESUMO
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
Assuntos
Caprolactama/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Serpinas/síntese química , Proteínas Virais/síntese química , Animais , Disponibilidade Biológica , Caprolactama/química , Caprolactama/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Interleucina-1beta/metabolismo , Masculino , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Serpinas/farmacologia , Relação Estrutura-Atividade , Proteínas Virais/farmacologiaRESUMO
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed.
Assuntos
Piperazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
The first synthesis of Tic-D-Phe Psi[CH(2)-CH(2)] isostere is described, which features diastereoselective alkylation of the tricyclic lactam 14. The use of this novel dipeptide isostere in the development of melanocortin agonists has been demonstrated by the synthesis of peptidomimetic 7 and non-peptidic ligand 27. Both compounds displayed significant binding and agonist potency at the MC4R.
Assuntos
Dipeptídeos/síntese química , Dipeptídeos/metabolismo , Fenilalanina/química , Receptor Tipo 4 de Melanocortina/agonistas , Alquilação , Dipeptídeos/química , Humanos , Lactamas/química , Ligantes , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Receptor Tipo 3 de Melanocortina/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.
Assuntos
Fármacos Antiobesidade/síntese química , Hormônios Hipotalâmicos/antagonistas & inibidores , Melaninas/antagonistas & inibidores , Hormônios Hipofisários/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Fármacos Antiobesidade/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Pirimidinonas , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazepinas/síntese química , Tiazepinas/farmacologia , Caspase 1/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiazepinas/químicaRESUMO
Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
Assuntos
Amidas/síntese química , Amidas/farmacologia , Aminoimidazol Carboxamida/síntese química , Inibidores de Caspase , Hidrazinas/síntese química , Hidrazinas/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Caspase 8 , Química Farmacêutica/métodos , Cisteína Endopeptidases/metabolismo , Indústria Farmacêutica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
The design and synthesis of a series of potent 1,3,4-trisubstituted-2-oxopiperazine based MC4 agonists are described. The tripeptidomimetic analogs (12a,b and 23) and the dipeptidomimetic 27 displayed single-nanomolar binding affinity and agonist potency for MC4R and excellent selectivity for MC4R relative to MC1R.
Assuntos
Desenho de Fármacos , Guanidinas/química , Guanidinas/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Guanidinas/síntese química , Estrutura Molecular , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-AtividadeRESUMO
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).
Assuntos
Obesidade/tratamento farmacológico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Ligação Competitiva/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Piperidinas/química , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Caspase , Peptídeos Cíclicos/farmacologia , Animais , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Concentração Inibidora 50 , Mimetismo Molecular , Peptídeos Cíclicos/síntese química , Pró-Fármacos/farmacocinética , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of proline based melanocortin ligands has been developed on the basis of initial piperazine leads by using a more conformationally rigid scaffold. A number of these novel ligands showed significant binding affinity for MC3 and MC4 receptors.
Assuntos
Prolina/química , Receptores de Melanocortina/efeitos dos fármacos , Desenho de Fármacos , Humanos , Ligantes , Prolina/farmacologia , Receptores de Melanocortina/metabolismo , EstereoisomerismoRESUMO
The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.
Assuntos
Inibidores de Caspase , Dipeptídeos/síntese química , Pirimidinonas/síntese química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacologia , Concentração Inibidora 50 , Mimetismo Molecular , Monócitos , Pirimidinonas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.
Assuntos
Dipeptídeos/síntese química , Interleucina-1/antagonistas & inibidores , Peptídeos Cíclicos/síntese química , Inibidores de Caspase , Dipeptídeos/química , Dipeptídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Interleucina-1/biossíntese , Conformação Molecular , Mimetismo Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.