RESUMEN
This paper describes the Structural and Physico-Chemical Interpretation (SPCI) approach, which is an extension of a recently reported method for interpretation of quantitative structure-activity relationship (QSAR) models. This approach can efficiently be used to reveal structural motifs and the major physicochemical factors affecting the investigated properties. Its efficacy was demonstrated both on the classical Free-Wilson data set and on several data sets with different end points (permeability of the blood-brain barrier, fibrinogen receptor antagonists, acute oral toxicity). Structure-activity patterns extracted from QSAR models with SPCI were in good correspondence with experimentally observed relationships and molecular docking, regardless of the machine learning method used. Comparison of SPCI with the matched molecular pair (MMP) method clearly shows an advantage of our approach over MMP, especially for small or structurally diverse data sets. The developed approach has been implemented in the SPCI software tool with a graphical user interface, which is publicly available at http://qsar4u.com/pages/sirms_qsar.php .
Asunto(s)
Fenómenos Químicos , Biología Computacional/métodos , Relación Estructura-Actividad Cuantitativa , Administración Oral , Animales , Barrera Hematoencefálica/metabolismo , Minería de Datos , Diseño de Fármacos , Oligopéptidos/química , Peptidomiméticos/química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacología , Peptidomiméticos/toxicidad , Permeabilidad , Ratas , Receptores Fibrinógenos/antagonistas & inhibidores , Programas Informáticos , Pruebas de Toxicidad , Interfaz Usuario-ComputadorRESUMEN
The C9-C20 segment of the fibrinogen receptor inhibitor tetrafibricin was prepared in 10 steps (longest linear sequence). Ruthenium catalyzed enantioselective syn-crotylation is used to construct C9-C13. Iridium catalyzed asymmetric alcohol C-H allylation of a commercial malic acid derived alcohol is used to construct C14-C20. Recovery and recycling of the iridium catalyst is described.
Asunto(s)
Alcoholes/química , Iridio/química , Macrólidos/química , Receptores Fibrinógenos/antagonistas & inhibidores , Receptores Fibrinógenos/química , Catálisis , Enlace de Hidrógeno , Macrólidos/farmacología , Estructura Molecular , EstereoisomerismoRESUMEN
The leukocyte ß2 integrin Mac-1 (CD11b/CD18) plays a pivotal role in inflammation and host defense. To develop peptide antagonists selectively inhibiting the function of Mac-1, we used a random constrained 6-mer (cys-6aa-cys) peptide library to map the structural features of CD11b, by determining the epitope of neutralizing monoclonal antibody mAb 44a (anti-CD11b). We have used a stringent phage display strategy, which resulted in the identification of one disulfide C-RLKEKH-C constrained peptide by direct biopanning of library on decreasing amounts of purified mAb 44a. The selected peptide mimics a discontinuous epitope, a peculiar shape on the CD11b-I-domain surface. Competitive ELISA experiments with different Mac-1 ligands showed that C-RLKEKH-C is able to bind to fibrinogen, iC3b, and C1q. Furthermore, the monomeric circular peptide C-RLKEKH-C, was effective in blocking the interaction between (125)I-fibrinogen and Mac-1 (IC(50)=3.35±0.1×10(-6)M), and inhibited the adhesion of human neutrophils to fibrinogen and iC3b. These data provide information about the relative location of amino acids on the I-domain surface using mAb 44a imprint of the CD11b protein. The derived mimotope may help in the design of future anti-inflammatory therapeutic agents that can act as specific therapeutic agents targeting PMNs mediated inflammation.
Asunto(s)
Antígeno CD11b/genética , Antígenos CD18/genética , Mapeo Epitopo/métodos , Fibrinógeno/metabolismo , Antígeno de Macrófago-1/genética , Péptidos/metabolismo , Receptores Fibrinógenos/antagonistas & inhibidores , Antiinflamatorios/química , Antiinflamatorios/farmacología , Anticuerpos Monoclonales , Sitios de Unión , Antígeno CD11b/metabolismo , Antígenos CD18/química , Antígenos CD18/metabolismo , Adhesión Celular , Complemento C3b/metabolismo , Humanos , Antígeno de Macrófago-1/química , Antígeno de Macrófago-1/metabolismo , Neutrófilos/metabolismo , Biblioteca de Péptidos , Péptidos/antagonistas & inhibidores , Péptidos/química , Péptidos Cíclicos/antagonistas & inhibidores , Unión ProteicaRESUMEN
The novel RGD mimetics with phthalimidine central fragment were synthesized with the use of 4-piperidine-4-yl-butyric, 4-piperidine-4-yl-benzoic, 4-piperazine-4-yl-benzoic and 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acids as surrogates of Arg motif. The synthesized compounds potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to α(IIb)ß(3) integrin in a suspension of washed human platelets. The key α(IIb)ß(3) protein-ligand interactions were determined in docking experiments.
Asunto(s)
Diseño de Fármacos , Ftalimidas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Receptores Fibrinógenos/antagonistas & inhibidores , Arginina/análogos & derivados , Arginina/metabolismo , Plaquetas/metabolismo , Evaluación Preclínica de Medicamentos , Fibrinógeno/metabolismo , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Ligandos , Oligopéptidos/química , Oligopéptidos/metabolismo , Inhibidores de Agregación Plaquetaria/química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Receptores Fibrinógenos/metabolismo , Programas Informáticos , Estereoisomerismo , Relación Estructura-Actividad , Tirofibán , Tirosina/análogos & derivados , Tirosina/química , Tirosina/metabolismoRESUMEN
The complex and widespread family of integrin receptors is involved in numerous physiological processes, such as tissue remodeling, angiogenesis, development of the immune response and homeostasis. In addition, their key role has been elucidated in important pathological disorders such as cancer, cardiovascular diseases, osteoporosis, autoimmune and inflammatory diseases and in the pathogenesis of infectious diseases, making them highly important targets for modern drug design campaigns. In this review we seek to present a concise overview of the small molecule antagonists of this diverse and highly complex receptor family. Integrin antagonists are classified according to the targeted integrin receptor and are discussed in four sections. First we present the fibrinogen alpha(IIb)beta3 and the vitronectin alpha (V)beta(3) receptor antagonists. The remaining selective integrin antagonists are examined in the third section. The final section is dedicated to molecules with dual or multiple integrin activity. In addition, the use of antibodies and peptidomimetic approaches to modulate the integrin receptors are discussed, as well providing the reader with an overall appreciation of the field.
Asunto(s)
Integrinas/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Humanos , Receptores Fibrinógenos/antagonistas & inhibidores , Receptores de Vitronectina/antagonistas & inhibidoresRESUMEN
It has been proposed a novel method for obtaining of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid as Arg-mimetic within the framework of search for novel fibrinogen receptor antagonists. New alpha (IIb)beta(3) antagonists were prepared on a base of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid. Their high antiaggregatory activities in a human platelet rich plasma and ability to block FITC-Fg binding to alpha (IIb)beta(3) on washed human platelets were estimated.
Asunto(s)
Receptores Fibrinógenos/antagonistas & inhibidores , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Fibrinógeno/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oligopéptidos/antagonistas & inhibidores , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Plasma Rico en Plaquetas/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Receptores Fibrinógenos/metabolismo , Tetrahidroisoquinolinas/químicaRESUMEN
There is evidence linking raised plasma fibrinogen (fib) and platelet hyperactivity with vascular events. One way to inhibit platelets is to block the platelet membrane glycoprotein (GP) IIb/IIIa receptor, which binds circulating fib or von Willebrand factor and cross-links platelets at the final common pathway to platelet aggregation. Tirofiban is a potent and specific fib receptor antagonist, used in the treatment of unstable angina. The authors assessed the effect of tirofiban on spontaneous platelet aggregation (SPA), fib-induced, serotonin (5HT)-induced, and adenosine diphosphate (ADP)-induced aggregation in whole blood by calculating the percentage free platelet count. These various agonists were used alone and in combination. The authors also measured the effect of tirofiban on agonists-induced (ADP, 5HT) platelet shape change (PSC). The effect of fib on PSC was also evaluated in platelet-rich plasma using a high-resolution (0.07 fL) channelyzer. Tirofiban significantly inhibited SPA, fib (2, 4, 8 g/L), ADP, ADP + fib combination, and 5HT-induced aggregation. Tirofiban had no effect on agonist-induced PSC. There was no apparent change in platelet volume with fib. In conclusion, tirofiban does not appear to have an effect on PSC, an early phase of platelet activation. Tirofiban seems to be a nonspecific and an effective inhibitor of platelet aggregation (a later phase of platelet activation) in whole blood. The clinical significance of these findings remains to be established.
Asunto(s)
Plaquetas/efectos de los fármacos , Fibrinolíticos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Tirosina/análogos & derivados , Adenosina Difosfato/farmacología , Plaquetas/citología , Forma de la Célula/efectos de los fármacos , Fibrinógeno/agonistas , Humanos , Técnicas In Vitro , Agregación Plaquetaria/efectos de los fármacos , Receptores Fibrinógenos/antagonistas & inhibidores , Serotonina/farmacología , Tirofibán , Tirosina/farmacologíaRESUMEN
Peptide leads D-Phe-Pro-Arg for thrombin inhibition and Arg-Gly-Asp for antagonistic activity on fibrinogen receptor were combined in one molecule in order to produce compounds capable of acting both as thrombin inhibitors and as fibrinogen receptor antagonists. Peptide conjugate 7 possessing both leads joined by a tetraglycine linker as well as tripeptides and peptidomimetics with highly overlapped D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups were prepared. Conjugate 7 was found to possess antagonistic activity on fibrinogen receptor, but was unexpectedly inactive as thrombin inhibitor. Compound 9 comprising of highly integrated D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups was found to possess a moderate but well balanced thrombin inhibitory and fibrinogen receptor antagonistic activity.
Asunto(s)
Anticoagulantes/farmacología , Inhibidores Enzimáticos/farmacología , Oligopéptidos/química , Péptidos/farmacología , Trombina/antagonistas & inhibidores , Secuencia de Aminoácidos , Anticoagulantes/síntesis química , Anticoagulantes/química , Sitios de Unión , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Fibrinógeno/antagonistas & inhibidores , Fibrinógeno/química , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Agregación Plaquetaria/efectos de los fármacos , Receptores Fibrinógenos/antagonistas & inhibidores , Receptores Fibrinógenos/química , Estereoisomerismo , Relación Estructura-Actividad , Trombina/químicaRESUMEN
Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.
Asunto(s)
Arginina/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Imitación Molecular , Diseño de Fármacos , Integrina alfaVbeta3/antagonistas & inhibidores , Modelos Moleculares , Óxido Nítrico Sintasa/antagonistas & inhibidores , Receptores Fibrinógenos/antagonistas & inhibidoresRESUMEN
Two novel RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydro-isoquinoline-7-yl)amino-4-oxo-butyric acid as a new surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alphaIIbbeta3 on washed human platelets.
Asunto(s)
Receptores Fibrinógenos/antagonistas & inhibidores , Isoquinolinas , Espectroscopía de Resonancia Magnética , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
The novel fibrinogen receptor antagonists containing fragments of 7-amino-1,2,3,4-tetrahydroisoquinoline and isophthalic acids were synthesized and successfully tested for their ability to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alpha(IIb)beta(3) on washed human platelets.
Asunto(s)
Ácidos Ftálicos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Receptores Fibrinógenos/antagonistas & inhibidores , Unión Competitiva/efectos de los fármacos , Bioensayo , Evaluación Preclínica de Medicamentos , Humanos , Imitación Molecular , Estructura Molecular , Ácidos Ftálicos/síntesis química , Ácidos Ftálicos/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel class of potential antithrombotic compounds with moderate thrombin inhibitory and fibrinogen receptor antagonistic activity is described. Combination of anticoagulant and antiaggregatory activity in the same molecular entity is presented as a new promising approach in the search for novel antithrombotic agents.
Asunto(s)
Anticoagulantes/síntesis química , Benzoxazinas/síntesis química , Fibrinolíticos/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Receptores Fibrinógenos/antagonistas & inhibidores , Trombina/antagonistas & inhibidores , Anticoagulantes/química , Anticoagulantes/farmacología , Benzoxazinas/química , Benzoxazinas/farmacología , Inhibidores del Factor Xa , Fibrinógeno/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacología , Modelos Moleculares , Imitación Molecular , Peso Molecular , Oligopéptidos/química , Péptidos/química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismoRESUMEN
New platelet glycoprotein IIb/IIIa (GP IIb/IIIa, integrin alpha(IIb)beta3) antagonists were prepared on a 2H-1,4-benzoxazine-3(4H)-one scaffold. Their anti-aggregatory activities in human platelet rich plasma and their affinity towards alpha(IIb)beta3 and alpha(V)beta3 integrins were assessed. Various substitution positions and side chain variations were studied. In contrast to the generally accepted model, compounds containing ethyl esters as aspartate mimetics were in general more active than the corresponding free acids. We suggest an explanation for the observed behaviour of these new compounds.
Asunto(s)
Benzoxazinas/síntesis química , Plaquetas/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Receptores Fibrinógenos/antagonistas & inhibidores , Ácido Aspártico , Benzoxazinas/farmacología , Sitios de Unión , Plaquetas/química , Diseño de Fármacos , Integrina alfaVbeta3 , Imitación Molecular , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Controversial results have been reported concerning the ability of fibrinogen receptor antagonists (fibans) to induce conformational changes in the fibrinogen receptor after binding to it as the initial step of fibrinogen binding and platelet activation. METHODS: Platelets in citrated whole blood were stained with several pairs of anti-glycoprotein (anti-GP) IIb-directed monoclonal antibodies conjugated to phycoerythrin (PE) or indirectly labeled with Cy5. Pairs of monoclonal antibodies that induced a high-fluorescence resonance energy transfer (FRET) efficiency served as tools to detect activation-dependent changes of GP IIb after addition of adenosine diphosphate and several fibans. RESULTS: Using the combination of the clones 5B12-PE and P2-biotin/SA-Cy5, a concentration-dependent alteration of the GP IIb conformation was observed after addition of tirofiban, eptifibatide, and lotrafiban. Magnitude and kinetics differed among the investigated substances. CONCLUSION: The newly developed FRET assay allows the direct investigation of conformational changes of GP IIb after addition of platelet agonists or receptor ligands, as shown for three fibans.
Asunto(s)
Plaquetas/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Glicoproteína IIb de Membrana Plaquetaria/efectos de los fármacos , Receptores Fibrinógenos/antagonistas & inhibidores , Anticuerpos Monoclonales/metabolismo , Plaquetas/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Transferencia Resonante de Energía de Fluorescencia/métodos , Humanos , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ficoeritrina/metabolismo , Activación Plaquetaria/efectos de los fármacos , Glicoproteína IIb de Membrana Plaquetaria/metabolismo , Conformación Proteica/efectos de los fármacos , Receptores Fibrinógenos/metabolismoRESUMEN
The novel RGDF mimetics 9a and 9b were synthesized with the use of 4-(isoindoline-5-yl)amino-4-oxobutyric acid as a surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alpha(IIb)beta(3) on washed human platelets.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacología , Indoles/síntesis química , Indoles/farmacología , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Receptores Fibrinógenos/antagonistas & inhibidores , Butiratos/química , Evaluación Preclínica de Medicamentos , Humanos , Indoles/química , Isoindoles , Imitación Molecular , Estructura Molecular , Oligopéptidos/química , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.
Asunto(s)
Péptidos/síntesis química , Prolina/análogos & derivados , Receptores Fibrinógenos/antagonistas & inhibidores , Unión Competitiva , Integrinas/química , Mediciones Luminiscentes , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Oligopéptidos/química , Oligopéptidos/farmacología , Péptidos/química , Péptidos/farmacología , Prolina/química , Receptores Fibrinógenos/química , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The platelet aggregation is a crucial step in a pathophisiology of thromboses, leading to development of cardio-vascular diseases (myocardial infarction, transient ischemic attacks, strokes, etc.). The final step in the aggregation is the binding of fibrinogen to receptor - glycoprotein IIb/IIIa (GP IIb/IIIa) on the surface of activated platelets. In recent years the increasing attention is paid to the role of fibrinogen antagonists in the prevention of thrombosis. The search for these compounds is based on the molecular design of structures mimicking some fragment of RGD (Arg-Gly-Asp) sequence, responsible for the binding of fibrinogen to GP IIb/IIIa. Up to now, a large number of potent and selective GP IIb/IIIa antagonists, including non-peptide inhibitors are identified (derivatives of benzodiazepines, aminobenzamidinosuccinyles, isoxazolines, isoquinolines). The modification of natural peptide structures for obtaining of more active and selective fibrinogen receptor antagonists is realized in several ways: substitution of main pharmacophores of RGD sequence; cyclization of RGD-containing peptides; design of conformationally constrained peptidomimetics. For the treatment of chronic cardio-vascular diseases, the clinic needs high orally active RGD-peptidomimetics. This task is realized by obtaining of prodrugs on the base of the most potent RGD-mimetics. In our laboratory the molecular design and synthesis of non-peptide fibrinogen receptor antagonists were carried out. The series of RGD-mimetics on the basis of 4-oxo-(piperazine-1-yl)butyric acid as Arg-mimetic and beta-aryl-beta-alanines as Asp-Phe-mimetics were synthesized. Obtained RGD-mimetics showed a high antiaggregatory activity in vitro experiments with IC(50)values of 10(-7) - 10(-9) M.
Asunto(s)
Oligopéptidos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Profármacos , Receptores Fibrinógenos/antagonistas & inhibidores , Animales , Biomimética , Plaquetas/metabolismo , Diseño de Fármacos , Fibrinógeno/metabolismo , Humanos , Estructura Molecular , Oligopéptidos/química , Inhibidores de Agregación Plaquetaria/química , Conformación Proteica , Relación Estructura-ActividadRESUMEN
The polymorphism Leu(33)-->Pro (platelet-specific antigen; Pl(A1/A2)) of platelet GPIIIa is a potential risk factor for arterial thrombosis. However, its influence on platelet function remains controversial and little is known about its impact on platelet sensitivity to GPIIb-IIIa antagonists. Our objective was to compare the effectiveness of various GPIIb-IIIa antagonists in Pl(A2)(+) and Pl(A2)(-) carriers. Platelet aggregation was monitored in healthy donors including Pl(A2)(-) (N=31) and Pl(A2)(+) subjects (N=27; 23 Pl(A1/A2), 4 Pl(A2)/(A2)) using the impedance and turbidimetric aggregation techniques. We evaluated the inhibition of ADP- and collagen-induced aggregation by disintegrins, kistrin and echistatin, and the low-molecular-weight blockers, GR144053F ((4-[4-[4-(aminoiminomethyl]-1-piperazinyl]-1-piperidineacetic acid, hydrochloride trihydrate) and eptifibatide (N(6)-(aminoiminomethyl)-N(2)-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-propyl-L-cysteinamide, cyclic (1-->6)-disulfide). Kistrin (10-30 nmol/l) inhibited ADP- and collagen-induced aggregation stronger in Pl(A2)(-) donors than in Pl(A2)(+) donors; there was a significant difference between 50% inhibitory concentrations (IC(50)). The same tendency occurred with moderate concentrations of eptifibatide (40-100 nmol/l) and also at low concentrations of GR144053F (5-10 nmol/l) and high concentrations of echistatin (80-150 nmol/l), although in the case of the two latter inhibitors, the estimated IC(50) values were not significantly different. In conclusion, GPIIb-IIIa blockers representing various classes are less effective inhibitors of platelet aggregation in Pl(A2)(+) carriers; however, the effect of the genotype is both agonist- and antagonist-dependent.