RESUMO
A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.
Assuntos
Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ureia/químicaRESUMO
Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
Assuntos
Oxidiazóis/síntese química , Piridazinas/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Acil Coenzima A/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of novel stearoyl-CoA desaturase 1 (SCD1) inhibitors were identified by scaffold design based on known SCD1 inhibitors. Large structural changes were made leading to multiple analogs with comparable or improved potency. This approach is valuable for generation of proprietary compounds without conducting a costly high-throughput screening.
Assuntos
Inibidores Enzimáticos/farmacologia , Etilaminas/farmacologia , Piperidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Etilaminas/síntese química , Piperidinas/síntese química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The hemodynamic effects of a series of potent and selective 4-aminopyridine carboxamide-based pan-JNK inhibitors were assessed in an anesthetized rat model. The effects of these agents on mean arterial pressure, heart rate, cardiac contractility, and peripheral vascular resistance are described, and the implication for targeting protein kinases in metabolic diseases is discussed.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , MAP Quinase Quinase 4/antagonistas & inibidores , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/enzimologia , Contração Miocárdica/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Anestesia , Anestésicos , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiopental/análogos & derivados , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
Assuntos
Amidas/síntese química , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , TermodinâmicaRESUMO
The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.
Assuntos
Aminopiridinas/síntese química , Fármacos Antiobesidade/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacologia , Aminopiridinas/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/síntese química , Depressores do Apetite/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores de Grelina , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologiaRESUMO
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
Assuntos
Aminopiridinas/síntese química , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Meia-Vida , Humanos , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/química , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Fosforilação , Conformação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.
Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Grelina , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
The synthesis and structure-activity relationships of the 4- and 6-substituents of 2,4-diaminopyrimidine-based growth hormone secretagogue receptor (GHS-R) antagonists are described. Diaminopyrimidines with 6-norbornenyl (4n) and 6-tetrahydrofuranyl (4p) substitutents were found to exhibit potent GHS-R antagonism and good selectivity (approximately 1000-fold) against dihydrofolate reductase.
Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Pirimidinas/química , Receptores de Grelina , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacosRESUMO
A series of isoxazole carboxamide derivatives has been developed as potent ghrelin receptor antagonists. The synthesis and structure-activity relationship (SAR) are described.
Assuntos
Amidas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Amidas/metabolismo , Amidas/farmacologia , Animais , Disponibilidade Biológica , Humanos , Concentração Inibidora 50 , Isoxazóis/síntese química , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Microssomos Hepáticos/metabolismo , Ratos , Receptores de Grelina , Relação Estrutura-AtividadeRESUMO
Guided by X-ray crystallography, we have extended the structure-activity relationship (SAR) study on an isoxazole carboxylic acid-based PTP1B inhibitor (1) and more potent and equally selective (>20-fold selectivity over the highly homologous T-cell PTPase, TCPTP) PTP1B inhibitors were identified. Inhibitor 7 demonstrated good cellular activity against PTP1B in COS 7 cells.