RESUMEN
A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC50=85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50=1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. Cmax after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A(y) mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , PPAR gamma/agonistas , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/química , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidroisoquinolinas/sangre , Tetrahidroisoquinolinas/químicaRESUMEN
A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-2-[(2E,4E)-hexadienoyl]-7-(2-{5-methyl-2-[(1E)-5-methylhexen-1-yl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14i) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ) selective agonist (EC(50)=0.03 µM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 µM). C(max) after oral administration of 14i at 10mg/kg was 2.2 µg/ml (4.5 µM) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED(50)=4.3 and 23 mg/kg/day, respectively, in male KK-A(y) mice. In female SD rats, repeated administration of 14i at 12.5-100mg/kg/day for 28 days had no effect on the hematocrit value (Ht) and red blood cell count (RBC), while rosiglitazone significantly decreased them from 25mg/kg/day. In conclusion, 14i showed about a fivefold stronger hypoglycemic effect and fourfold or more weaker hemodilution effect than rosiglitazone, indicating that 14i is 20-fold or more safer than rosiglitazone. Compound 14i is a promising candidate for an efficacious and safe anti-diabetic drug targeting PPARγ and PTP-1B.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Oxazoles/química , Oxazoles/farmacología , PPAR gamma/agonistas , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Hipoglucemiantes/síntesis química , Isoquinolinas/síntesis química , Masculino , Ratones , Oxazoles/síntesis química , PPAR gamma/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacologíaRESUMEN
2-Acyl-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2,4-Hexadienoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14) showed peroxisome proliferator-activated receptor γ (PPARγ) and PPARα agonist activities and protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activities. PPARγ agonist activity of 14 was comparable to that of rosiglitazone, and PTP-1B inhibitory activity was about 10-fold weaker than that of ertiprotafib, a PTP-1B inhibitor. Compound 14 showed high oral absorption in rats and potent hypoglycemic effects in KK-A(y) mice. In conclusion, 14 would be an excellent lead compound for a new type of anti-diabetic drug with triple actions.
Asunto(s)
Hipoglucemiantes/química , PPAR alfa/agonistas , PPAR gamma/agonistas , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Tetrahidroisoquinolinas/química , Administración Oral , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacologíaRESUMEN
Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARγ (EC50=0.14 µM) and was much higher than in human PPARα (EC50=0.20 µM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC50=1.85 µM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-Ay mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Receptores Activados del Proliferador del Peroxisoma/agonistas , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Quinazolinonas/farmacología , Tetrahidroisoquinolinas/farmacología , Animales , Glucemia/efectos de los fármacos , Ácidos Carboxílicos/química , Cricetinae , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Ratones Endogámicos ICR , Terapia Molecular Dirigida , Quinazolinonas/síntesis química , Quinazolinonas/química , Rosiglitazona , Tetrahidroisoquinolinas/efectos adversos , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Tiazolidinedionas/farmacologíaRESUMEN
Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice. Acetylcholine (ACh), adenosine-5'-diphosphate (ADP), NaF, a G protein activator and A-23187, a Ca-ionophore, caused endothelium-dependent and nitric oxide (NO)-mediated relaxation, and sodium nitroprusside (SNP), an NO donor, caused endothelium-independent relaxation in the pre-contracted aorta of db/db mice. Maximal endothelium-dependent ACh-induced relaxation was reduced in diabetic but not pre-diabetic db/db mice compared to age-matched db/+ mice, while maximal SNP-induced relaxation was not different between diabetic and non-diabetic mice. ACh-induced relaxation in diabetic db/db mice was not affected by ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, or acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor, suggesting no involvement of endogenous TXA2 or prostanoids in the reduction of relaxation. Maximal endothelium-dependent ADP-, A-23187-, and NaF-induced relaxation was not reduced in diabetic db/db mice. EC50 values for ACh- and SNP-induced relaxation were increased in diabetic but not pre-diabetic db/db mice, suggesting decreases in sensitivity to NO in diabetic mice. Two-week treatment with KV-5070, a PPARgamma agonist, lowered plasma glucose, triglyceride (TG), and insulin but not cholesterol, and reversed the reduced ACh-induced relaxation. In conclusion, ACh-induced endothelium-dependent relaxation is impaired in diabetic db/db mice, probably due to the dysfunction of ACh receptors and/or receptor-G protein coupling. Endothelial dysfunction was not genetic and was considered to be initiated primarily by hyperglycemia, and was improved by anti-diabetic treatment with a PPARgamma agonist.
Asunto(s)
Acetilcolina/farmacología , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/metabolismo , Vasodilatadores/farmacología , Animales , Aorta Torácica/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Hiperglucemia/fisiopatología , Hiperinsulinismo/fisiopatología , Hiperlipidemias/fisiopatología , Masculino , Ratones , Óxido Nítrico/metabolismo , PPAR gamma/agonistas , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Tetrahidroisoquinolinas/farmacologíaRESUMEN
First total syntheses of (+)-secosyrins 1 and 2 and total syntheses of (+)-syributins 1 and 2 are described. The two chiral centers of diisopropyl tartrate were incorporated into target natural products. Stereoselective construction of the spiro skeleton of secosyrins could be realized by taking advantage of an alkyne-cobalt complex. The synthesis of these compounds established their relative and absolute stereochemistry unambiguously.
RESUMEN
A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10, KY-021) was identified as a novel peroxisome proliferators-activated receptor (PPAR) gamma agonist, which showed potent activity in human PPAR gamma (EC50=11.8 nM). KY-021 reduced plasma glucose and triglyceride levels at 3 mg/kg/d for 7 d in male KK-Ay mice. KY-021 also decreased plasma triglyceride levels at 0.3-3 mg/kg/d for 6 d, and improved oral glucose tolerance at 1 and 3 mg/kg/d for 7 d in male Zucker fatty rats. Maximal plasma concentration of KY-021 after oral administration at 10 mg/kg was 6.6 microg/ml and 2.1 microg/ml in male ICR mice and male SD rats, respectively. Repeated oral administration of KY-021 at 30 mg/kg/d for 10 weeks had little toxicity in male SD rats. These results demonstrated that KY-021 has great potential as an efficacious and safe drug for diabetes.