The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Tamio Ueno - One of the best experts on this subject based on the ideXlab platform.
-
Three-dimensional quantitative structure-activity relationship analyses of RGD mimetics as Fibrinogen Receptor antagonists.
Bioorganic & medicinal chemistry letters, 2000Co-Authors: Masahiro Miyashita, Miki Akamatsu, Yoshio Hayashi, Tamio UenoAbstract:In order to better understand the structural requirements of Fibrinogen Receptor antagonists, variations in the platelet aggregation inhibitory activity of a series of RGD mimetics were examined using techniques for the analysis of three-dimensional quantitative structure activity relationship, such as CoMFA.
-
Structure-activity relationships of RGD mimetics as Fibrinogen-Receptor antagonists.
Bioscience biotechnology and biochemistry, 1999Co-Authors: Masahiro Miyashita, Miki Akamatsu, Hideki Ueno, Yoshiaki Nakagawa, Keiichiro Nishimura, Yoshio Hayashi, Yoshimi Sato, Tamio UenoAbstract:The activities of a series of RGD mimetics, which contained a variety of cationic structures, for the inhibition of platelet aggregation and Fibrinogen-Receptor binding were measured. The stability of the coulombic ion-pairing complex of the model compounds with the acetate anion as a model for the Receptor was calculated in terms of the ionic interaction energy. The results suggest that stability is one of the significant factors which govern the inhibitory potency of Fibrinogen-Receptor binding. The distance between cationic and anionic groups might also affect the potency. A compound which contained an amidinophenyl structure as the cationic moiety showed exceptionally high inhibitory activity, suggesting that some other factors, in addition to coulombic interaction and the distance, affect the potency.
Robert J. Gould - One of the best experts on this subject based on the ideXlab platform.
-
antiplatelet effects of mk 852 a platelet Fibrinogen Receptor antagonist in healthy volunteers
The Journal of Clinical Pharmacology, 2000Co-Authors: Howard E Greenberg, Robert J. Gould, Paul Wissel, Jeffrey S Barrett, Aaron Barchowsky, Daniel Farrell, Deborah Panebianco, Elizabeth HandAbstract:MK-852, a cyclic heptapeptide, is a potent platelet Fibrinogen Receptor antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.44 microgram/kg/min for 4 hours, respectively, MK-852 extended baseline bleeding time by greater than 2.2-fold and 2.6-fold, inhibited ADP-induced platelet aggregation by 76% and 69%, and inhibited collagen-induced platelet aggregation by 65% and 67%, respectively. The pharmacokinetics of MK-852 include an elimination half-life of approximately 2 hours, total clearance of about 150 ml/min, and volume of distribution of about 18 liters. Examination of the relationship between MK-852 whole-blood concentration in vitro and inhibition of platelet aggregation showed an EC50 of about 55 ng/ml and a Hill coefficient of 1.55. The infusions were generally well tolerated, with no study drug-related changes in blood counts or biochemical profiles.
-
Fibrinogen Receptor antagonist induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug dependent antibodies to platelet glycoprotein iib iiia
Blood, 1999Co-Authors: Bohumil Bednar, George D. Hartman, Jacquelynn J. Cook, Rodney A Bednar, Marie A Holahan, Michael E Cunningham, Patricia A Jumes, Robert J. GouldAbstract:Most clinical trials with Fibrinogen Receptor antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738,167 and L-739,758. However, an equally efficacious antiaggregatory dose of another potent antagonist, L-734,217, caused no change in platelet count. These compounds did not affect platelet count in five other chimpanzees or numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of chimpanzees, humans, and all other primates tested only in the presence of the compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different antagonist, L-767,679, and several prodrugs that are converted into the active form, L-767,679, in the blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again identified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 human subjects with L-738,167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% ± 0.6% and 1.1% ± 0.6%, respectively.
-
nonpeptide glycoprotein iib iiia inhibitors 13 design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
-
non peptide glycoprotein iib iiia inhibitors 17 design and synthesis of orally active long acting non peptide Fibrinogen Receptor antagonists
Journal of Medicinal Chemistry, 1997Co-Authors: B. C. Askew, Robert J. Gould, Jacquelynn J. Cook, Charles J. Mcintyre, David A. Claremon, Robert J. Lynch, Rodney A Bednar, Bohumil Bednar, Cecila A Hunt, Joseph J. LynchAbstract:The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide Fibrinogen Receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to Fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
-
Nonpeptide glycoprotein IIb/IIIa inhibitors. 13. design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
Timothy J Foster - One of the best experts on this subject based on the ideXlab platform.
-
identification of the ligand binding domain of the surface located Fibrinogen Receptor clumping factor of staphylococcus aureus
Molecular Microbiology, 1995Co-Authors: Damien Mcdevitt, Patrice Francois, Pierre Vaudaux, Timothy J FosterAbstract:The ability of Staphylococcus aureus to bind to Fibrinogen and fibrin is believed to be an important factor in the initiation of foreign-body and wound infections. Recently, we reported the cloning and sequencing of the gene clfA encoding the Fibrinogen Receptor (clumping factor, ClfA) of S. aureus strain Newman and showed that the gene product was responsible for the clumping of bacteria in soluble Fibrinogen and for the adherence of bacteria to solid-phase Fibrinogen. This was confirmed here by showing that antibodies raised against purified Region A inhibited both of these properties. Also, immunofluorescent microscopic analysis of wild-type Newman and a clfA::Tn917 mutant of Newman with anti-ClfA Region A sera confirmed that Region A is exposed on the bacterial cell surface. Furthermore, polystyrene beads coated with the Region A protein formed clumps in soluble Fibrinogen showing that the ClfA protein alone is sufficient for the clumping phenotype. Western immunoblotting with anti-ClfA Region A antibodies identified the native ClfA Receptor as a 185 kDa protein that was released from the cell wall of S. aureus by lysostaphin treatment. A single extensive ligand-binding site was located within Region A of the ClfA protein. Truncated ClfA proteins were expressed in Escherichia coli. Lysates of E. coli and proteins that had been purified by affinity chromatography were tested for (i) their ability to bind Fibrinogen in Western ligand blotting experiments, (ii) for their ability to inhibit clumping of bacteria in Fibrinogen solution and adherence of bacteria to solid-phase Fibrinogen, and (iii) for their ability to neutralize the blocking activity of anti-ClfA Region A antibody. These tests allowed the ligand-binding domain to be localized to a 218-residue segment (residues 332-550) within Region A.
-
molecular characterization of the clumping factor Fibrinogen Receptor of staphylococcus aureus
Molecular Microbiology, 1994Co-Authors: Damien Mcdevitt, Patrice Francois, Pierre Vaudaux, Timothy J FosterAbstract:Four mutants of Staphylococcus aureus strain Newman that were defective in the Fibrinogen Receptor (clumping factor) were isolated by transposon Tn917 mutagenesis. Southern hybridization analysis of the mutants identified transposon-host DNA junction fragments, one of which was cloned and used to generate a probe to identify and clone the wild-type clumping factor locus (clfA). The mutants failed to form clumps in soluble Fibrinogen and adhered poorly to polymethylmethacrylate (PMMA) coverslips coated with Fibrinogen. A single copy of the clfA gene, when introduced into the chromosome of the mutant strains, fully complemented the clumping deficiency of these strains and restored the ability of these mutants to adhere to Fibrinogen-coated PMMA. In addition, the cloned clfA gene on a shuttle plasmid allowed the weakly clumping strain 8325-4 to form clumps with the same avidity as the wild-type strain Newman and also significantly enhanced the adherence of 8325-4 strains. Thus the formation of clumps in soluble Fibrinogen correlated with adherence of bacteria to solid-phase Fibrinogen. The clfA gene encodes a Fibrinogen-binding protein with an apparent molecular mass of c. 130 kDa. The amino acid sequence of the protein was deduced from the DNA sequence; it was predicted that a 896 residue protein (molecular mass 92 kDa) would be expressed. The putative ClfA protein has features that suggest that it is associated with the cell surface. Furthermore it contains a novel 308 residue region comprising dipeptide repeats predominantly of Asp and Ser ending 28 residues upstream from the LPXTG motif common to wall-associated proteins. Significant homology was found between the ClfA protein and the fibronectin-binding proteins of S. aureus, particularly in the N- and C-termini.
Bernard Maigret - One of the best experts on this subject based on the ideXlab platform.
-
Elucidation of a common structure of selective Fibrinogen Receptor antagonists
Journal of Computer-Aided Molecular Design, 1998Co-Authors: Hervé Minoux, Nicolas Moitessier, Yves Chapleur, Bernard MaigretAbstract:In this paper, we investigate the common structural and electrostatic parameters of a series of specific inhibitors of the αIIbβ3 integrin. Molecular dynamics simulations with an explicit aqueous environment led to an original theoretical pattern. Our results may suggest that the studied non-peptide αIIbβ3 antagonists developed upon the Arg-Gly-Asp ubiquitous recognition sequence, in fact, should mimic the C-terminus part of the Fibrinogen γ chain. This assumption could, therefore, explain their specificity with respect to other Arg-Gly-Asp-dependent integrins.
-
Synthesis of carbohydrate-based peptidomimetics as potential selective Fibrinogen Receptor antagonists
Letters in Peptide Science, 1998Co-Authors: Nicolas Moitessier, Hervé Minoux, Bernard Maigret, Françoise Chrétien, Yves ChapleurAbstract:Modeling studies of several known antagonists of the Fibrinogen Receptor have provided a theoretical pattern of the essential characteristics for high affinity and selectivity toward this Receptor. Potentially active and selective antagonists of the Fibrinogen Receptor were thus designed by computational comparison of their aqueous conformations with that of known selective antagonists, and synthesized by grafting suitable functional groups on a D-xylose scaffold.
-
Design of specific antagonists of the Fibrinogen Receptor
Letters in Peptide Science, 1997Co-Authors: Hervé Minoux, Nicolas Moitessier, Yves Chapleur, Bernard MaigretAbstract:The aim of this work was to elucidate, usingmolecular modeling, structural and electrostaticcommon parameters of several selective FibrinogenReceptor antagonists. From this theoretical pattern,we are currently designing and synthesizing originalnon-peptidic and selective carbohydrate-basedantagonists of the Fibrinogen Receptor.
Jacquelynn J. Cook - One of the best experts on this subject based on the ideXlab platform.
-
Fibrinogen Receptor antagonist induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug dependent antibodies to platelet glycoprotein iib iiia
Blood, 1999Co-Authors: Bohumil Bednar, George D. Hartman, Jacquelynn J. Cook, Rodney A Bednar, Marie A Holahan, Michael E Cunningham, Patricia A Jumes, Robert J. GouldAbstract:Most clinical trials with Fibrinogen Receptor antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738,167 and L-739,758. However, an equally efficacious antiaggregatory dose of another potent antagonist, L-734,217, caused no change in platelet count. These compounds did not affect platelet count in five other chimpanzees or numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of chimpanzees, humans, and all other primates tested only in the presence of the compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different antagonist, L-767,679, and several prodrugs that are converted into the active form, L-767,679, in the blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again identified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 human subjects with L-738,167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% ± 0.6% and 1.1% ± 0.6%, respectively.
-
nonpeptide glycoprotein iib iiia inhibitors 13 design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
-
non peptide glycoprotein iib iiia inhibitors 17 design and synthesis of orally active long acting non peptide Fibrinogen Receptor antagonists
Journal of Medicinal Chemistry, 1997Co-Authors: B. C. Askew, Robert J. Gould, Jacquelynn J. Cook, Charles J. Mcintyre, David A. Claremon, Robert J. Lynch, Rodney A Bednar, Bohumil Bednar, Cecila A Hunt, Joseph J. LynchAbstract:The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide Fibrinogen Receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to Fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
-
Nonpeptide glycoprotein IIb/IIIa inhibitors. 13. design and synthesis of an orally active pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonist
Bioorganic & Medicinal Chemistry Letters, 1997Co-Authors: B. C. Askew, Robert J. Gould, Paul S. Anderson, C.c. Chang, Charles J. Mcintyre, Cecilia A. Hunt, David A. Claremon, J. J. Baldwin, R. J. Lynch, Jacquelynn J. CookAbstract:Abstract The synthesis and antiplatelet activity of a series of pyrazolopiperazinone nonpeptide Fibrinogen Receptor antagonists is reported. The sulfonamide analog 6 (L-734, 115), significantly inhibited ex vivo platelet aggregation 24 h after oral administration at doses of 1.0 and 2.0 mg/kg to dogs and rhesus monkeys, respectively.
-
Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist
Journal of medicinal chemistry, 1995Co-Authors: Mark E. Duggan, Robert J. Gould, Adel M. Naylor-olsen, James J. Perkins, Paul S. Anderson, C.c. Chang, Jacquelynn J. Cook, Nathan C. Ihle, George D. HartmanAbstract:The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active Fibrinogen Receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human, dog, and chimpanzee platelets at concentrations below 100 nM and was found to be > 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to Fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.