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1.
Bioorg Med Chem Lett ; 20(4): 1388-94, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20097563

RESUMO

Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.


Assuntos
Fibrinolíticos/farmacologia , Ácido Glutâmico/síntese química , Piperidinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Fibrinolíticos/síntese química , Fibrinolíticos/química , Ácido Glutâmico/química , Ácido Glutâmico/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Ratos , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 19(16): 4657-63, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19604694

RESUMO

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.


Assuntos
Ácido Glutâmico/química , Piperazinas/química , Inibidores da Agregação Plaquetária/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Piridinas/química , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 19(21): 6148-56, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19796941

RESUMO

Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.


Assuntos
Fibrinolíticos/química , Ácido Glutâmico/química , Piperidinas/química , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2 , Pirimidinas/química , Animais , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Humanos , Masculino , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade
5.
Curr Opin Drug Discov Devel ; 8(6): 757-75, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16312151

RESUMO

Polymer-assisted solution-phase (PASP) synthesis has become a prevalent method for the parallel synthesis of chemical libraries. PASP methodology enables the chemist to prepare libraries of compounds more quickly and efficiently than previously. PASP technology encompasses a number of purification techniques for intermediate and final product purification. This methodology continues to progress, providing the practitioner with a broad range of ingenious purification methods, enabling multi-step syntheses of complex compounds. This review covers significant new advances in the use of tagged-reagents/substrates, resin capture-release techniques and PASP multi-step synthesis, some of which incorporate microwave heating and automation.


Assuntos
Compostos Orgânicos/síntese química , Polímeros/química , Antracenos/química , Automação , Quelantes/química , Precipitação Química , Técnicas de Química Combinatória , Óxidos N-Cíclicos/química , Indicadores e Reagentes/química , Resinas de Troca Iônica/química , Micro-Ondas , Compostos Orgânicos/isolamento & purificação , Fosfinas , Soluções
6.
J Med Chem ; 46(22): 4696-701, 2003 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-14561089

RESUMO

Targeted 2-pyridones were selected as tissue Factor VIIa inhibitors and prepared from 2,6-dibromopyridine via a multistep synthesis. A variety of chemical transformations, including regioselective nucleophilic addition, selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue Factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa enzyme. These compounds were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue Factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of inhibitor 14a bound to tissue Factor VIIa was obtained and will be described.


Assuntos
Acetamidas/síntese química , Benzoatos/síntese química , Fator VIIa/antagonistas & inibidores , Inibidores de Proteases/síntese química , Piridonas/síntese química , Acetamidas/química , Benzoatos/química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Piridonas/química , Relação Estrutura-Atividade
7.
J Med Chem ; 46(20): 4297-312, 2003 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-13678408

RESUMO

Several multistep syntheses of substituted benzenes are reported. The benzene analogues were designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa enzyme. A variety of chemical transformations including nucleophilic additions, reductive aminations, Stille couplings, and polymer-assisted solution-phase (PASP) techniques were used to prepare key intermediates and final products. The initial analogues identified some weakly active compounds which ultimately led to a 340 nM (IC(50)) tissue Factor VIIa inhibitor with selectivity over other related enzymes. The structure-activity relationship of these inhibitors and the synthetic progression from the discovery of the lead compound to the development of potent analogues will be discussed. The X-ray crystal structures of fluorobenzene 50c and benzoquinone 54 inhibitors complexed with the TF/VIIa enzyme will also be described.


Assuntos
Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/farmacologia , Fator VIIa/antagonistas & inibidores , Derivados de Benzeno/química , Benzoquinonas/química , Sítios de Ligação , Cristalografia por Raios X , Fator VIIa/genética , Inibidores do Fator Xa , Humanos , Modelos Moleculares , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores
8.
J Med Chem ; 46(19): 4043-9, 2003 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-12954057

RESUMO

A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification concepts, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multistep synthesis affords desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of tissue Factor VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10k bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin.


Assuntos
Técnicas de Química Combinatória/métodos , Fator VIIa/antagonistas & inibidores , Cetonas/química , Tiazóis/síntese química , Tiazóis/farmacologia , Tromboplastina/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Fator VIIa/genética , Fator VIIa/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Polímeros/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo , Trombina/antagonistas & inibidores , Trombina/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo
9.
J Med Chem ; 46(19): 4050-62, 2003 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-12954058

RESUMO

Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250 x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.


Assuntos
Fator VIIa/antagonistas & inibidores , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Tromboplastina/antagonistas & inibidores , Antitrombina III/farmacologia , Sítios de Ligação , Técnicas de Química Combinatória/métodos , Cristalografia por Raios X , Desenho de Fármacos , Fator VIIa/química , Fator VIIa/genética , Fibrinolíticos/química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Pirazinas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Trombina/antagonistas & inibidores , Tromboplastina/química
10.
Thromb Res ; 112(3): 167-74, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14967414

RESUMO

INTRODUCTION: Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation. MATERIALS AND METHODS: PHA inhibits the TF/VIIa complex with an IC(50) of 13.5 nM (K(i) 9 nM) and is more than 2000-fold selective for the TF/VIIa complex with respect to IC(50)s for factor Xa and thrombin. In the model, a thrombogenic surface was introduced into the vena cava of a primate, and the amount of thrombus accumulated after 30 min was determined. RESULTS: PHA-798 reduced thrombus formation on the thrombogenic surface in a dose-dependent manner (56+/-1.9% and 85+/-0.3% inhibition with 100 and 200 microg/kg/min PHA-798, respectively) indicating that the model is sensitive to TF/VIIa inhibition. Treatment with 1 mg/kg intravenous (IV) acetyl salicylic acid (ASA) resulted in only a slight (4-12%), non-significant inhibition of thrombus formation. However, the combination of 100 microg/kg/min PHA-798 and 1 mg/kg ASA resulted in an 89% inhibition of thrombus formation. Additionally, while ASA alone increased bleeding time (BT) from 3.3 min at baseline to 4.6 min following treatment, addition of PHA-798 (100 microg/kg/min) to ASA did not significantly increase the BT further (4.7 min). CONCLUSIONS: The results of this study indicate that inhibition of TF/VIIa may be safe and effective for the prevention of the proprogation of venous thrombosis and that the combination of ASA and PHA may provide increased efficacy with little change in safety.


Assuntos
Fator VIIa/antagonistas & inibidores , Tromboplastina/antagonistas & inibidores , Trombose/fisiopatologia , Animais , Aspirina/toxicidade , Tempo de Sangramento , Peso Corporal , Modelos Animais de Doenças , Macaca fascicularis , Masculino , Inibidores da Agregação Plaquetária/toxicidade , Trombose/sangue , Trombose/induzido quimicamente
11.
J Pharmacol Toxicol Methods ; 49(1): 31-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14670692

RESUMO

INTRODUCTION: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. METHODS: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. RESULTS: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. DISCUSSION: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.


Assuntos
Guanidinas/efeitos adversos , Liberação de Histamina/efeitos dos fármacos , Hipotensão/induzido quimicamente , Pirazinas/efeitos adversos , Animais , Cromolina Sódica/efeitos adversos , Cromolina Sódica/farmacologia , Guanidinas/farmacologia , Hipotensão/fisiopatologia , Injeções Intravenosas , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , p-Metoxi-N-metilfenetilamina/efeitos adversos , p-Metoxi-N-metilfenetilamina/farmacologia
12.
J Med Chem ; 53(5): 2010-37, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20141147

RESUMO

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.


Assuntos
Piperazinas/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2 , Piridinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Feminino , Glutamatos/síntese química , Glutamatos/farmacocinética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Piperazinas/síntese química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Piridinas/síntese química , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Relação Estrutura-Atividade , Adulto Jovem
13.
J Org Chem ; 68(25): 9678-86, 2003 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-14656094

RESUMO

A general method for polymer-assisted solution-phase (PASP) Suzuki reactions employing a combination of anthracene-tagged palladium catalyst and anthracene-tagged boronic acid with a polymer-supported carbonate base is reported. The anthracene-tagged catalyst allows for the easy removal of the Pd catalyst along with the dissociated phosphine ligand and phosphine oxide byproducts by sequestration through a chemoselective Diels-Alder reaction with a maleimide resin. The polymer-supported carbonate base facilitates the removal of excess boronic acid and the borane-containing byproducts present at the end of the coupling reaction. The Suzuki coupling reaction can be efficiently conducted by using combinations of the anthracene-tagged Pd catalyst, polymer-supported carbonate base, and anthracene-tagged boronic acid to yield the desired product in high purity and yield without the use of chromatography.

14.
Bioorg Med Chem Lett ; 13(21): 3721-5, 2003 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-14552766

RESUMO

Multistep syntheses of substituted benzenes and benzoquinone inhibitors of tissue Factor VIIa are reported. The benzene analogues were designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa (TF/VIIa) enzyme. The compounds exhibited modest potency on TF/VIIa with selectivity over Factor Xa and thrombin. The X-ray crystal structures of the targeted fluorobenzene 12a and benzoquinone 14 inhibitors bound to TF/VIIa were obtained and will be described.


Assuntos
Benzoquinonas/síntese química , Benzoquinonas/farmacologia , Fator VIIa/antagonistas & inibidores , Fluorbenzenos/síntese química , Fluorbenzenos/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Indicadores e Reagentes , Cetonas , Modelos Moleculares , Especificidade por Substrato
15.
Pharmacology ; 70(2): 100-6, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14685013

RESUMO

This study in non-human primates was designed to evaluate the bleeding propensity of a selective, small molecule inhibitor of tissue factor (TF)/VIIa in combination with acetylsalicylic acid (ASA) in comparison to the combination of ASA and warfarin. Bleeding time was increased by ASA but was not prolonged further by the addition of the TF/VIIa inhibitor, PHA-927, at doses that elevated the prothrombin time to 8-fold. In contrast, bleeding time was prolonged by warfarin alone and further exacerbated by the presence of ASA. Acute blood loss at the bleeding site, while not significantly increased by either warfarin or PHA-927, was increased substantially in several individuals treated with a combination of warfarin and ASA but not by the combination of TF/VIIa inhibitor and ASA. These data predict that TF/VIIa inhibition, in the presence of chronic aspirin therapy in patients with cardiovascular risk factors, will be a safe therapy for thrombotic disorders.


Assuntos
Aminobenzoatos/farmacologia , Anticoagulantes/farmacologia , Aspirina/farmacologia , Fator VIIa/antagonistas & inibidores , Inibidores da Agregação Plaquetária/farmacologia , Pirazinas/farmacologia , Tromboplastina/antagonistas & inibidores , Varfarina/farmacologia , Animais , Tempo de Sangramento , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Hemorragia/sangue , Macaca fascicularis , Masculino , Tempo de Protrombina , Tempo de Coagulação do Sangue Total
16.
J Pharmacol Exp Ther ; 306(3): 1115-21, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12829728

RESUMO

This study was designed to evaluate the antithrombotic efficacy and bleeding propensity of a selective, small-molecule inhibitor of tissue factor/factor VIIa (TF/VIIa) in comparison to small-molecule, selective inhibitors of factor Xa and thrombin in a nonhuman primate model of thrombosis. Acute, spontaneous thrombus formation was induced by electrolytic injury to the intimal surface of a femoral blood vessel, which results in thrombus propagation at the injured site. The TF/FVIIa inhibitor 3-amino-5-[1-[2-([4-[amino(imino)methyl]benzyl]amino)-2-oxoethyl]-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoic acid dihydrochloride (PHA-927F) was fully effective in prevention of thrombosis-induced vessel occlusion at a dose of 400 microg/kg/min, i.v., in the arterial vasculature (femoral artery). Neither the effective dose nor multiples up to 4.4-fold the effective arterial plasma concentration elicited any significant effect on bleeding time or blood loss from either the bleeding time site or the surgical (femoral isolation) site. Small-molecule inhibitors of factor Xa or thrombin were effective arterial antithrombotic agents; however, in contrast to the TF/FVIIa inhibitor, they both elicited substantial increases in bleeding propensity at the effective dose and at multiples of the effective plasma concentration. These data indicate that TF/VIIa inhibition effectively prevented arterial thrombosis with less impact on bleeding parameters than equivalent doses of factor Xa and thrombin inhibitors.


Assuntos
Aminobenzoatos/uso terapêutico , Fator VIIa/antagonistas & inibidores , Inibidores do Fator Xa , Fibrinolíticos/uso terapêutico , Pirazinas/uso terapêutico , Trombose/tratamento farmacológico , Animais , Tempo de Sangramento , Relação Dose-Resposta a Droga , Antebraço/fisiologia , Hemodinâmica/efeitos dos fármacos , Macaca fascicularis , Masculino , Tempo de Protrombina , Cloreto de Sódio , Trombina/antagonistas & inibidores , Tromboplastina/antagonistas & inibidores
17.
Bioorg Med Chem Lett ; 13(14): 2363-7, 2003 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-12824035

RESUMO

A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-L-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue factor VIIa, with some analogues demonstrating selectivity versus thrombin.


Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Fator VIIa/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Cristalografia por Raios X , Inibidores do Fator Xa , Humanos , Indicadores e Reagentes , Modelos Moleculares , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores
18.
Bioorg Med Chem Lett ; 13(14): 2319-25, 2003 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-12824026

RESUMO

Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P(2) surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P(1) and P(3) moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC(50) against TF/VIIa with >6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis.


Assuntos
Fator VIIa/antagonistas & inibidores , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores do Fator Xa , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Biblioteca de Peptídeos , Protrombina/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombose/sangue , Trombose/induzido quimicamente , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologia
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