RESUMEN
Several series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones with acidic sulfonamide replacements of tetrazole at the 2'-position of the biphenyl-4-ylmethyl side chain at N4 were prepared and tested as angiotensin II (AII) antagonists. Preferred substituents on the triazolinone ring were n-butyl at C5 and 2-(trifluoromethyl)phenyl at N2. Subnanomolar IC50 values at the AT1 receptor subtype were observed for a variety of acylsulfonamides, including aroyl, heteroaroyl, and cycloalkylcarbonyl derivatives. Certain other acidic sulfonamides, such as sulfonylcarbamates and disulfimides also displayed high affinity for the AT1 receptor. In addition, AT2 binding for some of these compounds was increased by as much as 1000-fold over the corresponding tetrazole (e.g., AT2 IC50 17 nM for the tert-butyl sulfonylcarbamate 92). When evaluated for inhibition of the AII pressor response, the benchmark benzoylsulfonamide 9 (L-159,913) was efficacious in several species and was superior to losartan (1a) in conscious rhesus monkeys. Several subsequent analogues, including the 2-chlorobenzoyl (18), (3-chlorothiophene-2-yl)carbonyl (51), ((S)-2,2-dimethylcyclopropyl)carbonyl (80), and tert-butoxycarbonyl (92) derivatives, were highly effective in rats, surpassing 9 and losartan in duration of action and/or potency. Compound 18 (L-162,223) displayed very prolonged AII antagonism in the rat model (> 24 h at 1 mg/kg iv). At 1 mg/kg po in rats, 18 and 92 (L-162,234) produced 85-87% peak inhibition of the AII pressor response with duration exceeding 6 h. The identification of triazolinone-based sulfonamide derivatives combining high AT1 affinity, considerably enhanced AT2 potency, and favorable in vivo properties provides insights relevant to the design of dual AT1/AT2 receptor antagonists.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Receptores de Angiotensina/metabolismo , Sulfonamidas/síntesis química , Triazoles/síntesis química , Antagonistas de Receptores de Angiotensina , Animales , Aorta/metabolismo , Indicadores y Reactivos , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Mesencéfalo/metabolismo , Estructura Molecular , Músculo Liso Vascular/metabolismo , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
MK-996, N-(4'-(5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl- methyl)1,1'-biphenyl-2-yl)-sulfonylbenzamide, is a potent, orally active, highly selective, nonpeptide angiotensin II (AII) receptor antagonist. MK-996 prevents the pressor response to intravenous AII in the conscious rat, dog, and rhesus monkey (ED50, mg/kg; oral/intravenous = 0.067/0.014, 0.035/0.017, and 0.1/0.036, respectively). In the anesthetized chimpanzee, MK-996 (1 mg/kg, iv) produces 100% (peak) inhibition of the AII pressor response and is still active (52%) at 24 h. To our knowledge this pharmacologic profile in the rat, dog, rhesus monkey, and chimpanzee presents the least species variability of any AII receptor antagonist yet described. Responses to methoxamine and arginine vasopressin are not affected by MK-996. In aortic coarcted (high renin) rats, MK-996 (3 mg/kg, by mouth) reduces blood pressure to normotensive (< 120 mm Hg) levels without reflex tachycardia. This dose of MK-996 reduces blood pressure to approximately the same level as both losartan (3 mg/kg, by mouth) and enalapril (3 mg/kg, by mouth) in this model. The duration of antihypertensive activity of MK-996 is similar to enalapril and shorter than losartan at the doses tested. Additionally, in the rat MK-996 does not potentiate the vasodepressor response to bradykinin and completely prevents the ability of AII to stimulate an increase in plasma levels of aldosterone. Therefore, MK-996 is a potent, orally active, nonpeptide AII receptor antagonist with a long duration of action, little species variability, and anti-hypertensive activity.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Imidazoles/farmacología , Piridinas/farmacología , Administración Oral , Aldosterona/sangre , Angiotensina II/antagonistas & inhibidores , Animales , Compuestos de Bifenilo/farmacología , Bradiquinina/farmacología , Perros , Enalapril/farmacología , Femenino , Inyecciones Intravenosas , Losartán , Macaca mulatta , Masculino , Nitroglicerina/farmacología , Pan troglodytes , Ratas , Ratas Sprague-Dawley , Tetrazoles/farmacologíaRESUMEN
L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.
Asunto(s)
Dioxoles/farmacología , Antagonistas de los Receptores de Endotelina , Imidazoles/farmacología , Animales , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Células CHO/efectos de los fármacos , Células CHO/metabolismo , Cricetinae , Dioxoles/metabolismo , Dioxoles/toxicidad , Perros , Endotelinas/antagonistas & inhibidores , Endotelinas/metabolismo , Endotelinas/farmacología , Femenino , Hurones , Humanos , Hidrólisis , Imidazoles/metabolismo , Imidazoles/toxicidad , Técnicas In Vitro , Radioisótopos de Yodo , Cinética , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Fosfatidilinositoles/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Endotelina/metabolismo , Relación Estructura-ActividadRESUMEN
[11C]L-159,884 ([11C] N-[[4'[(2-ethyl-5,7-dimethyl-3H- imidazo[4,5-b]pyridin-3-yl) methyl] [1,1'-biphenyl]-2-yl] sulfonyl]-4-methoxybenzamide) and [11C]L-162,574 ([11C] N-[[4'[2-ethyl-5,7- dimethyl-3H-imidazo[4,5-b] pyridin-3-yl)methyl] [1,1'-biphenyl]-2-yl]sulfonyl]-3- methoxybenzamide), both potent and selective ligands for the AT1 receptor, were prepared by C-11 methylation of the corresponding desmethyl phenolic precursors. The radiotracers were purified by semi-preparative reverse-phase HPLC. Non-decay corrected radiochemical yields were 5 and 3% for L-159,884 and L-162,574 respectively, and the average specific activity was 2979 mCi/mumol at end-of-synthesis (EOS). The average time of synthesis was 18 min.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Angiotensina I/metabolismo , Radioisótopos de Carbono/química , Imidazoles/metabolismo , Piridinas/metabolismo , Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina , Cromatografía Líquida de Alta Presión , Hidrocarburos Yodados/química , Procesamiento de Imagen Asistido por Computador , Imidazoles/síntesis química , Marcaje Isotópico/métodos , Piridinas/síntesis química , Tomografía Computarizada de EmisiónAsunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Imidazoles/farmacología , Piridinas/farmacología , Administración Oral , Animales , Antihipertensivos/síntesis química , Perros , Imidazoles/síntesis química , Macaca mulatta , Piridinas/síntesis química , RatasRESUMEN
Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacología , Fármacos Antiobesidad/farmacología , Oxadiazoles/farmacología , Sulfonamidas/farmacología , Agonistas Adrenérgicos beta/síntesis química , Agonistas Adrenérgicos beta/química , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Disponibilidad Biológica , Células CHO , Cricetinae , Perros , Diseño de Fármacos , Glicerol/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Macaca mulatta , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.
Asunto(s)
Agonistas Adrenérgicos beta/síntesis química , Receptores Adrenérgicos beta/metabolismo , Administración Oral , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacología , Animales , Perros , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Macaca mulatta , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos beta 3 , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The cyclopentylpropylimidazolidinone L-766,892 is a potent beta3 AR agonist (EC50 5.7 nM, 64% activation) with 420- and 130-fold selectivity over binding to the beta1 and beta2 ARs, respectively. In anesthetized rhesus monkeys, L-766,892 elicited dose-dependent hyperglycerolemia (ED50 0.1 mg/kg) with minimal effects on heart rate.
Asunto(s)
Agonistas Adrenérgicos beta/síntesis química , Ciclopentanos/síntesis química , Imidazoles/síntesis química , Receptores Adrenérgicos beta/metabolismo , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacología , Animales , Células CHO , Cricetinae , Ciclopentanos/farmacocinética , Ciclopentanos/farmacología , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Macaca mulatta , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos beta 3 , Relación Estructura-ActividadRESUMEN
The 3-pyridylethanolamine L-757,793 is a potent beta 3 AR agonist (EC50 6.3 nM, 70% activation) with 1,300- and 500-fold selectivity over binding to the beta 1 and beta 2 ARs, respectively. L-757,793 stimulated lipolysis in rhesus monkeys (ED50 0.2 mg/kg) with a maximum response equivalent to that elicited by isoproterenol.