Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 16(18): 4917-21, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16824753

RESUMO

A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.


Assuntos
Receptores de Somatostatina/antagonistas & inibidores , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Benzimidazóis/química , Humanos , Estrutura Molecular , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacocinética
2.
Proc Natl Acad Sci U S A ; 98(22): 12718-23, 2001 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-11606733

RESUMO

We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/farmacologia , HIV-1/efeitos dos fármacos , Piperidinas , Piridinas/farmacologia , Animais , Quimiocina CCL5/antagonistas & inibidores , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/uso terapêutico , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos SCID , Oximas , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
3.
J Med Chem ; 44(21): 3339-42, 2001 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-11585437

RESUMO

Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K(i) = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.


Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/síntese química , Piperazinas/síntese química , Piperidinas , Piridinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/virologia , Macaca fascicularis , Oximas , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 11(17): 2311-4, 2001 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-11527721

RESUMO

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.


Assuntos
Compostos de Benzilideno/química , Dioxóis/química , Dioxóis/farmacologia , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Acetilcolina/análise , Acetilcolina/metabolismo , Administração Oral , Animais , Área Sob a Curva , Compostos de Benzilideno/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Macaca fascicularis , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Antagonistas Muscarínicos/sangue , Ratos , Receptor Muscarínico M2 , Relação Estrutura-Atividade
5.
Circulation ; 103(14): 1899-905, 2001 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-11294810

RESUMO

BACKGROUND: Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries. METHODS AND RESULTS: An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13). CONCLUSIONS: Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.


Assuntos
Acetamidas/farmacologia , Doença das Coronárias/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina , Animais , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Doença das Coronárias/patologia , Doença das Coronárias/fisiopatologia , Vasos Coronários/patologia , Relação Dose-Resposta a Droga , Endotelina-1/metabolismo , Feminino , Radioisótopos do Iodo , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Peptídeos Cíclicos/farmacologia , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia
9.
J Am Soc Nephrol ; 8(7): 1061-71, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9219155

RESUMO

Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.


Assuntos
Acetamidas/farmacologia , Aorta/cirurgia , Antagonistas dos Receptores de Endotelina , Rim/efeitos dos fármacos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Animais , Constrição , Modelos Animais de Doenças , Cães , Endotelina-1/fisiologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/fisiologia , Circulação Renal/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos
10.
Mol Pharmacol ; 51(2): 301-11, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9203636

RESUMO

Two nonpeptide ligands that differ chemically by only a single methyl group but have agonistic (L-162,782) and antagonistic (L-162,389) properties in vivo were characterized on the cloned angiotensin AT1 receptor. Both compounds bound with high affinity (K(I) = 8 and 28 nM, respectively) to the AT1 receptor expressed transiently in COS-7 cells as determined in radioligand competition assays. L-162,782 acted as a powerful partial agonist, stimulating phosphatidylinositol turnover with a bell-shaped dose-response curve to 64% of the maximal level reached in response to angiotensin II. Surprisingly, L-162,389 also stimulated phosphatidylinositol turnover, albeit only to a small percentage of the angiotensin response. The prototype nonpeptide AT1 agonist L-162,313 gave a response of approximately 50%. The apparent EC50 values for all three compounds in stimulating phosphatidylinositol turnover were similar, approximately 30 nM, corresponding to their binding affinity. Each of the three compounds also acted as angiotensin antagonists, yet in this capacity the compounds differed markedly, with IC50 values ranging from 1.05 x 10(-7) M for L-162,389 to 6.5 x 10(-6) for L-162,782. A series of point mutations in the transmembrane segments (TMs) of the AT1 receptor had only minor effect on the binding affinity of the nonpeptide compounds, with the exception of A104V at the top of TM III, which selectively impaired the binding of L-162,782 and L-162,389. Substitutions in the middle of TM III, VI, or VII, which did not affect the binding affinity of the compounds, impaired or eliminated the agonistic efficacy of the nonpeptides but with only minor or no effect on the angiotensin potency or efficacy. Thus, in the N295D rat AT1 construct, L-162,782, L-162,313, and L-162,389 all antagonized the angiotensin-induced phosphatidylinositol turnover with surprisingly similar IC50 values (90-180 nM), and they all bound with unaltered, high affinity (22-36 nM). However, L-162,313 and L-162,782 could stimulate phosphatidylinositol turnover to only 20% of that of angiotensin. It is concluded that minor chemical modifications of either the compound or the receptor can dramatically alter the agonistic efficacy of biphenyl imidazole compounds on the AT1 receptor without affecting their affinity, as determined in binding assays, and that a number of substitutions in the middle of the TM segments affect the efficacy of nonpeptide agonists as opposed to angiotensin.


Assuntos
Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Mutação/genética , Receptores de Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Ligantes , Ratos , Receptores de Angiotensina/genética
11.
Circulation ; 93(5): 1009-19, 1996 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-8598064

RESUMO

BACKGROUND: Numerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin. METHODS AND RESULTS: In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg X kg-1 X d-1), L-163,082 (1 mg X kg-1 X d-1), or L-164,282 (1.5 mg X kg-1 X d-1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty. CONCLUSIONS: These findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2 antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.


Assuntos
Angiotensina II/fisiologia , Antagonistas de Receptores de Angiotensina , Doença das Coronárias/patologia , Vasos Coronários/efeitos dos fármacos , Imidazóis/farmacologia , Sulfonamidas/farmacologia , Tetrazóis/farmacologia , Angiotensina II/metabolismo , Animais , Vasos Coronários/patologia , Modelos Animais de Doenças , Imidazóis/sangue , Ratos , Recidiva , Suínos , Tetrazóis/sangue
13.
Life Sci ; 58(14): 1149-57, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8614266

RESUMO

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.


Assuntos
Dioxóis/farmacologia , Antagonistas dos Receptores de Endotelina , Imidazóis/farmacologia , Animais , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Células CHO/efeitos dos fármacos , Células CHO/metabolismo , Cricetinae , Dioxóis/metabolismo , Dioxóis/toxicidade , Cães , Endotelinas/antagonistas & inibidores , Endotelinas/metabolismo , Endotelinas/farmacologia , Feminino , Furões , Humanos , Hidrólise , Imidazóis/metabolismo , Imidazóis/toxicidade , Técnicas In Vitro , Radioisótopos do Iodo , Cinética , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Fosfatidilinositóis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Endotelina/metabolismo , Relação Estrutura-Atividade
14.
Eur J Pharmacol ; 294(2-3): 429-37, 1995 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-8750703

RESUMO

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl) [1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) inhibited specific 125I-[Sar1, Ile8]angiotensin II binding to angiotensin AT1 receptor (Ki = 0.11-0.20 nM) in rabbit aorta, rat adrenal and human angiotensin AT1 receptor in CHO (Chinese hamster ovary transformed) cells and to AT2 receptor (Ki = 0.14-0.23 nM) in rat adrenal and brain receptors. L-163,017 also had a high affinity in the presence of bovine serum albumin (2 mg/ml), for angiotensin AT1 and AT2 receptors on human adrenal (Ki 3.9 and 4.3 nM), aorta (Ki 0.45 and 0.96 nM) and kidney (Ki 3.6 and 2.3 nM). The much higher Ki values in human tissues were likely due to the presence of bovine serum albumin in the binding assay buffer since L-163,017 had Ki values of 0.13 +/- 0.04 and 2.0 +/- 0.04 nM in the absence and presence of bovine serum albumin, respectively, in inhibiting 125I-[Sar1,Ile8]angiotensin II binding to angiotensin AT1 receptor in rat adrenal membranes. Scatchard analysis of 125I-[Sar1,Ile8]angiotensin II binding in the presence of bovine serum albumin (2 mg/ml) in rabbit aorta and bovine cerebellum indicated a competitive interaction of L-163,017 with angiotensin AT1 and AT2 receptors (Ki values 2.5 and 2.1 nM respectively). L-163,017 inhibited angiotensin II-induced aldosterone release in rat adrenal demonstrating that L-163,017 acted as a competitive antagonist (pA2 = 9.9) and lacked agonist activity. L-163,017 also inhibited angiotensin II responses in rat vascular tissues. The specificity of L-163,017 was shown by its lack of activity on the above functional responses produced by other agonists and in several binding assays.


Assuntos
Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Imidazóis/farmacologia , Piridinas/farmacologia , Aldosterona/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Células CHO , Bovinos , Cricetinae , Humanos , Imidazóis/metabolismo , Técnicas In Vitro , Masculino , Piridinas/metabolismo , Coelhos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/metabolismo , Vasoconstrição/efeitos dos fármacos
15.
Eur J Pharmacol ; 294(2-3): 439-50, 1995 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-8750704

RESUMO

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.


Assuntos
Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Imidazóis/farmacologia , Piridinas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Imidazóis/metabolismo , Macaca mulatta , Masculino , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/metabolismo
16.
Clin Exp Hypertens ; 17(6): 931-53, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7581262

RESUMO

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2'-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydr o-2- [2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED50) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.


Assuntos
Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/farmacologia , Triazóis/farmacologia , Aldosterona/sangue , Angiotensina II/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Imidazóis/farmacologia , Rim/efeitos dos fármacos , Rim/fisiologia , Losartan , Macaca mulatta , Masculino , Natriurese/efeitos dos fármacos , Pan troglodytes , Potássio/urina , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Renina/fisiologia , Tetrazóis/farmacologia
17.
Am J Physiol ; 268(3 Pt 2): R820-3, 1995 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7900925

RESUMO

L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n- butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]- imadazo[4,5-b]pyridine) is a nonpeptide that mimics the biological actions of angiotensin II (ANG II). The intravenous administration of L-162,313 increased blood pressure in the rat. The maximum increase in mean arterial pressure (MAP) was not different from the maximum response to ANG II in the same preparation. However, the duration of the pressor response after L-162,313 greatly exceeded that of ANG II. Pretreatment with ANG II receptor antagonists, L-158,809 (AT1 selective) or saralasin, blocked the L-162,313-induced increase in MAP. Enalaprilat, an angiotensin-converting enzyme inhibitor, failed to block the MAP response to L-162,313. In vitro, L-162,313-activated phosphoinositide turnover in rat aortic smooth muscle cell cultures was also blocked by L-158,809 and losartan (DuP-753). Therefore, L-162,313 is the first reported nonpeptide ANG II receptor agonist.


Assuntos
Angiotensina II/agonistas , Compostos de Bifenilo/farmacologia , Imidazóis/farmacologia , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Células Cultivadas , Imidazóis/administração & dosagem , Imidazóis/química , Injeções Intravenosas , Ligantes , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fosfatidilinositóis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/agonistas , Receptores de Angiotensina/classificação , Receptores de Angiotensina/fisiologia
18.
J Biol Chem ; 270(4): 1493-6, 1995 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-7829475

RESUMO

Non-peptide ligands for peptide receptors for the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells transfected with the rat AT1 receptor a prototype of these compounds, L-162,313 stimulated phosphoinositide hydrolysis with an EC50 of 33 +/- 11 nM. The maximal response to the compound was 50% of that of angiotensin II in COS-7 cells but only 3% in stably transfected Chinese hamster ovary cells. The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells. In Chinese hamster ovary cells, L-162,313 also acted as an insurmountable antagonist of the angiotensin stimulated phosphoinositide hydrolysis. In contrast to previously tested non-peptide ligands, L-162,313 bound with reasonably high affinity to the Xenopus laevis AT1 receptor. In the human receptor, the binding of L-162,313 was found to be unaffected by point mutations in transmembrane segments III and VII, which impaired the binding of biphenylimidazole antagonists. Substitutions in the extracellular domains of the human and rat receptor, which impaired the binding of angiotensin II, did not affect the binding of L-162,313. It is concluded that a subset of biphenylimidazole compounds can act as high affinity partial agonists on the AT1 receptor. These compounds have molecular interactions with the receptor which appear to differ both from that of the structurally similar non-peptide antagonists and from that of their functional counterpart, the peptide agonist.


Assuntos
Angiotensinas/agonistas , Compostos de Bifenilo/farmacologia , Imidazóis/farmacologia , Fosfatos de Inositol/metabolismo , Fosfatidilinositóis/metabolismo , Receptores de Angiotensina/metabolismo , Sequência de Aminoácidos , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Animais , Ligação Competitiva , Compostos de Bifenilo/metabolismo , Células CHO , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Humanos , Imidazóis/metabolismo , Rim , Cinética , Ligantes , Dados de Sequência Molecular , Mutagênese Insercional , Mutação Puntual , Reação em Cadeia da Polimerase , Estrutura Secundária de Proteína , Ratos , Receptores de Angiotensina/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Tetrazóis/metabolismo , Tetrazóis/farmacologia , Transfecção , Xenopus laevis
19.
Am J Hypertens ; 8(1): 58-66, 1995 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7734099

RESUMO

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.


Assuntos
Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Piridinas/farmacologia , Administração Oral , Aldosterona/sangue , Angiotensina II/antagonistas & inibidores , Animais , Compostos de Bifenilo/farmacologia , Bradicinina/farmacologia , Cães , Enalapril/farmacologia , Feminino , Injeções Intravenosas , Losartan , Macaca mulatta , Masculino , Nitroglicerina/farmacologia , Pan troglodytes , Ratos , Ratos Sprague-Dawley , Tetrazóis/farmacologia
20.
J Biol Chem ; 269(49): 30953-9, 1994 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-7983030

RESUMO

To locate essential determinants for angiotensin II binding, we have performed a systematic mutational analysis of the exterior domain of the AT1 receptor. Receptor mutants, deficient in peptide binding, were analyzed using radiolabeled nonpeptide ligand as an important tool. Two independent strategies for mutagenesis were employed: conservative segment exchange and point mutagenesis of evolutionarily conserved residues. Results from the conservative segment exchange in which 6-17 residues were replaced with chemically similar, yet different, amino acid sequences of the same length suggested that important peptide ligand binding epitopes are located in the N-terminal extension of the AT1 receptor, in particular adjacent to the top of transmembrane segment I (TM-I), and in the third extracellular loop, close to the top of TM-VII. The substitution of residues from either of these regions resulted in a 5,000-20,000-fold decrease in affinity for the peptide agonist angiotensin II (AII) and the peptide antagonist [Sar1,Leu8]AII without affecting the binding of nonpeptide antagonists. Alanine substitution of evolutionarily conserved residues demonstrated that peptide binding was dependent on several residues in the N-terminal extension, near the top of TM-I, a tyrosine residue located in extracellular loop 1, close to TM-II, and 2 aspartate residues positioned in extracellular loop 3 on the same face of an alpha-helical extension of TM-VII. In all cases the binding of nonpeptide antagonist was unaffected by these substitutions. It is concluded that important epitopes involved in angiotensin II binding are located around the top of transmembrane segments I, II, and VII which conceivably are in close spatial proximity in the folded receptor structure.


Assuntos
Angiotensina I/metabolismo , Peptídeos/metabolismo , Receptores de Angiotensina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Evolução Biológica , Células Cultivadas , Sequência Conservada , Humanos , Dados de Sequência Molecular , Mutagênese , Ligação Proteica , Estrutura Secundária de Proteína , Ratos , Receptores de Angiotensina/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...