RESUMO
The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
Assuntos
Benzimidazóis/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Benzimidazóis/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Canal de Potássio ERG1 , Eletrofisiologia/métodos , Canais de Potássio Éter-A-Go-Go/química , Humanos , Hipnóticos e Sedativos/farmacologia , Concentração Inibidora 50 , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Morfolinas/química , Nitrogênio/química , Piperidinas/química , Receptores Histamínicos H1/química , Relação Estrutura-AtividadeRESUMO
In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.
Assuntos
Hidantoínas/farmacologia , Pirazóis/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Paladar/efeitos dos fármacos , Animais , Café/química , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Hidantoínas/síntese química , Hidantoínas/toxicidade , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Ratos , Relação Estrutura-AtividadeRESUMO
Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers.
Assuntos
Desenho de Fármacos , Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Ciclização , Estrutura Molecular , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Receptor Tipo 4 de Melanocortina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
Assuntos
Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Benzilaminas/síntese química , Benzilaminas/química , Células CACO-2 , Carcinoma Pulmonar de Lewis , Cristalografia por Raios X , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of piperazinephenethylamines were synthesized to study the contribution of a basic amine to binding affinity at the melanocortin-4 receptor. Several potent compounds from this series possessed subnanomolar K(i) values in a competition binding assay.
Assuntos
Fenetilaminas/química , Fenetilaminas/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Animais , Benzilaminas/metabolismo , Concentração Inibidora 50 , Cinética , Fenetilaminas/metabolismo , Piperazinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
Assuntos
Amidas/síntese química , Benzilaminas/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma Pulmonar de Lewis/complicações , Linhagem Celular , Cristalografia por Raios X , AMP Cíclico/metabolismo , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
Assuntos
Caquexia/tratamento farmacológico , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , beta-Alanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/etiologia , AMP Cíclico/metabolismo , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/complicações , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , beta-Alanina/síntese química , beta-Alanina/farmacocinética , beta-Alanina/farmacologiaRESUMO
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.
Assuntos
Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Disponibilidade Biológica , Humanos , Injeções Intravenosas , Ligação Proteica/fisiologia , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Ratos , Ratos Zucker , Receptor Tipo 4 de Melanocortina/metabolismoRESUMO
A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K(i) of 13 nM in binding affinity and EC(50) of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand alpha-MSH.
Assuntos
Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Linhagem Celular , HumanosRESUMO
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
Assuntos
Caquexia/tratamento farmacológico , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Composição Corporal , Peso Corporal , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pirrolidinonas/administração & dosagem , Pirrolidinonas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.
Assuntos
Pirrolidinonas/química , Pirrolidinonas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Alquilação , Aminas/química , Animais , Encéfalo/efeitos dos fármacos , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Animais , Benzilaminas/química , Humanos , Camundongos , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacocinética , Receptor Tipo 4 de Melanocortina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Dipeptídeos/química , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade , beta-Alanina/químicaRESUMO
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Amidas/química , Animais , Humanos , Ligantes , Camundongos , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Synthesis and structure-activity relationship studies of a series of cyclohexylpiperazines bearing an amide side chain as ligands of the MC4 receptor are discussed. Compounds such as 11i from this series are potent agonists (EC(50)=33nM, IA=96%).
Assuntos
Benzenoacetamidas/química , Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Humanos , Ligantes , Piperazinas/síntese química , Relação Estrutura-AtividadeRESUMO
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues.
Assuntos
Benzilaminas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Oral , Animais , Benzilaminas/administração & dosagem , Benzilaminas/química , Benzilaminas/farmacocinética , Disponibilidade Biológica , Linhagem Celular , Humanos , Camundongos , Piperazinas/químicaRESUMO
A series of cyclohexylpiperazines was synthesized as potent and selective antagonists of the human MC4 receptor. Compound 14t displayed binding affinity (Ki) of 4.2 and 1100 nM at MC4R and MC3R, respectively.
Assuntos
Amidas/química , Piperidinas/farmacologia , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Ligação Competitiva , Humanos , Conformação Molecular , Piperidinas/síntese química , Piperidinas/química , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compound 12e and the quinolin-3-ylcarbonyl analogue 12l possessed K(i) values of 6.3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM).
Assuntos
Benzilaminas/síntese química , Benzilaminas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Linhagem Celular , AMP Cíclico/análise , Relação Dose-Resposta a Droga , Humanos , Piperazina , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/genética , Relação Estrutura-Atividade , Transfecção , alfa-MSH/análiseRESUMO
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration.