RESUMO
Novel pyrrole derivatives were discovered as potent agonists of the niacin receptor, GPR109A. During the derivatization, compound 16 was found to be effective both in vitro and in vivo. The compound 16 exhibited a significant reduction of the non-esterified fatty acid in human GPR109A transgenic rats, and the duration of its in vivo efficacy was much longer than niacin.
Assuntos
Agonistas Nicotínicos/química , Pirróis/química , Receptores Acoplados a Proteínas G/agonistas , Animais , Desenho de Fármacos , Ácidos Graxos não Esterificados/metabolismo , Humanos , Lipólise/efeitos dos fármacos , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Pirróis/metabolismo , Pirróis/farmacologia , Ratos , Ratos Transgênicos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50=2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.
Assuntos
Esterol Esterase/antagonistas & inibidores , Administração Oral , Animais , Dislipidemias/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Concentração Inibidora 50 , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability.
Assuntos
Desenho de Fármacos , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Esterol Esterase/antagonistas & inibidores , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Administração Oral , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Glutationa/química , Glutationa/metabolismo , Glicerol/sangue , Meia-Vida , Humanos , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Concentração Inibidora 50 , Masculino , Ratos , Ratos Wistar , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Esterol Esterase/genética , Esterol Esterase/metabolismo , Relação Estrutura-AtividadeRESUMO
Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3mg/kg.
Assuntos
Ácidos Borônicos/farmacologia , Inibidores Enzimáticos/farmacologia , Esterol Esterase/antagonistas & inibidores , Administração Oral , Animais , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Piperidinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Piridazinas/uso terapêutico , Estearoil-CoA Dessaturase/antagonistas & inibidores , Alanina Transaminase/sangue , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Piperidinas/farmacologia , Substâncias Protetoras/farmacologia , Piridazinas/farmacologia , Ratos , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismoRESUMO
Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis.
Assuntos
Benzopiranos/síntese química , Piperidinas/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/farmacocinética , Estearoil-CoA Dessaturase/metabolismoRESUMO
Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd).
Assuntos
Inibidores Enzimáticos/química , Hipoglicemiantes/química , Piperidinas/química , Piridazinas/química , Piridinas/química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Triglicerídeos/sangue , Administração Oral , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Camundongos , Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Piperidinas/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Ratos Zucker , Estearoil-CoA Dessaturase/metabolismoRESUMO
The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
Assuntos
Benzamidas/síntese química , Química Farmacêutica/métodos , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tiazóis/síntese química , Administração Oral , Animais , Área Sob a Curva , Benzamidas/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Químicos , Estearoil-CoA Dessaturase/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of structurally novel stearoyl-CoA desaturase-1 (SCD-1) inhibitors has been identified by optimizing a hit from our corporate library. Preliminary structure-activity relationship (SAR) studies led to the discovery of the highly potent and orally bioavailable thiazole-based SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a).
Assuntos
Benzamidas/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tiazóis/síntese química , Administração Oral , Animais , Área Sob a Curva , Benzamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Químicos , Estearoil-CoA Dessaturase/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
BACKGROUND AND AIMS: Nicotinic acid administration causes plasma non-esterified fatty acid (NEFA) reduction and plasma lipid changes, including reduced triglyceride levels. GPR109A, which is expressed mainly in adipose tissue and has anti-lipolytic activity, was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding. Therefore, whether GPR109A activation can lead to plasma lipid changes is unclear. METHODS: We created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat) and examined the in vivo role of GPR109A. RESULTS: Under fasted conditions, plasma NEFA and triglyceride levels in Tg rats were lower than those in non-Tg rats. In this condition, a positive correlation between plasma NEFA and triglyceride or ß-hydroxybutyrate levels was observed. Furthermore, insulin levels in Tg rats were lower than those in non-Tg rats only when a reduction in NEFAs was observed, which is a phenomenon also reported for nicotinic acid. Interestingly, body weight gain in Tg rats was significantly lower than in non-Tg rats. CONCLUSIONS: These results suggest that GPR109A signaling leads to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid is at least partially mediated by GPR109A signaling.
Assuntos
Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Triglicerídeos/sangue , Animais , Peso Corporal , Cromossomos Artificiais Bacterianos , Ácidos Graxos não Esterificados/sangue , Regulação da Expressão Gênica , Genótipo , Humanos , Hiperglicemia , Lipídeos/sangue , Lipólise , Fígado/metabolismo , Masculino , Niacina/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Nicotínicos/metabolismoRESUMO
1. We studied the effect of a new angiotensin II type 1 (AT(1)) receptor antagonist, olmesartan medoxomil (olmesartan), on the fibrogenic responses in rat hepatic stellate cells (HSCs) and liver fibrogenesis. 2. Olmesartan (1 mg kg(-1) per day) was orally administered to fibrotic rats, induced by bile duct ligation. Liver hydroxyproline content, the mRNA expression of collagen alpha1(I) and alpha-smooth muscle actin (alpha-SMA), and plasma levels of transforming growth factor-beta1 (TGF-beta1) were significantly reduced by olmesartan treatment, suggesting that olmesartan improved liver fibrosis. Interestingly, AT(1) receptors were found to be expressed in alpha-SMA-positive cells in the fibrotic area of livers in bile duct-ligated rats by immunohistochemical analysis. Olmesartan treatment reduced the number of these cells. 3. In vitro experiments showed that angiotensin II (Ang II) treatment induced proliferation and collagen synthesis, and upregulated the profibrogenic cytokines, TGF-beta1 and connective tissue growth factor (CTGF), in rat primary HSCs. Olmesartan blocked all these effects of Ang II. 4. Based on these results, since activated HSCs were found to express AT(1) receptors and Ang II is thought to play an important role in the pathogenesis of liver fibrosis by binding to these receptors, olmesartan may act as a potent antifibrotic drug to suppress the proliferation, collagen synthesis and the expression of profibrogenic cytokines in activated HSCs by blocking these receptors.