RESUMO
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacologia , Aminas/química , Cloridrato de Atomoxetina , Sítios de Ligação , Linhagem Celular , Química Farmacêutica/métodos , Desipramina/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Propilaminas/química , Relação Estrutura-AtividadeRESUMO
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Indanos/síntese química , Indanos/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Cloridrato de Atomoxetina , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indanos/química , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Propilaminas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Receptores LHRH/antagonistas & inibidores , Uracila/análogos & derivados , Uracila/síntese química , Animais , Citocromo P-450 CYP3A , Haplorrinos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Uracila/farmacocinéticaRESUMO
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
Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure--activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K(i) value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 microM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
Assuntos
Caquexia/tratamento farmacológico , Desenho de Fármacos , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Tiofenos/síntese química , Animais , AMP Cíclico/biossíntese , Humanos , Masculino , Hormônios Estimuladores de Melanócitos/química , Camundongos , Modelos Moleculares , Mutagênese , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Tiofenos/farmacologiaRESUMO
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
Assuntos
Descoberta de Drogas , Hidrocarbonetos Fluorados/farmacologia , Pirimidinas/farmacologia , Receptores LHRH/antagonistas & inibidores , Animais , Células CACO-2 , Inibidores do Citocromo P-450 CYP3A , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/metabolismo , Macaca fascicularis , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/química , Pirimidinas/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
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 substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Assuntos
Química Farmacêutica/métodos , Cromonas/síntese química , Melaninas/química , Quinolonas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores do Hormônio Hipofisário/química , Administração Oral , Animais , Cromonas/química , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Quinolonas/química , Ratos , Fatores de TempoRESUMO
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 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
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Concentração Inibidora 50 , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
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
Treatment of various 2-methyl oxazolines or thiazolines with chlorocarbonyl isocyanate gives the corresponding bicyclic oxazolino- or thiazolino[3,2-c]pyrimidin-5,7-dione derivatives in very good yield. This reaction has been applied to the rapid syntheses of human gonadotropin-releasing hormone (hGnRH) receptor antagonists for SAR study, resulting in 13e with binding affinity in the low nanomolar range (4.5 nM).
Assuntos
Compostos Bicíclicos com Pontes , Oxazóis , Pirimidinonas , Receptores LHRH/antagonistas & inibidores , Tiazóis , Ligação Competitiva , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Ciclização , Humanos , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
Several efficient synthetic routes for 2-, 4-, and 6-aryl-1,2,4-triazine-3,5-diones were developed. Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds.
Assuntos
Receptores LHRH/antagonistas & inibidores , Triazinas/síntese química , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Triazinas/farmacologiaRESUMO
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
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
A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor.
Assuntos
Cetonas/síntese química , Receptores LHRH/antagonistas & inibidores , Triazinas/síntese química , Alquilação , Técnicas de Química Combinatória , Humanos , Ligação Proteica , 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
Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (Ki=0.45 nM).
Assuntos
Receptores LHRH/antagonistas & inibidores , Uracila/farmacologia , Humanos , Isomerismo , Estrutura Molecular , Uracila/química , Difração de Raios XRESUMO
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.