156185-58-9Relevant academic research and scientific papers
High-Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin
Piras, Monica,Testa, Andrea,Fleming, Ian N.,Dall'Angelo, Sergio,Andriu, Alexandra,Menta, Sergio,Mori, Mattia,Brown, Gavin D.,Forster, Duncan,Williams, Kaye J.,Zanda, Matteo
supporting information, p. 1142 - 1151 (2017/07/25)
Nonpeptidic Arg-Gly-Asp (RGD)-mimic ligands were designed and synthesized by click chemistry between an arginine–azide mimic and an aspartic acid–alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g., tritium and fluorine-18, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Lead compound 12 was successfully radiofluorinated and used for in vivo positron emission tomography/computed tomography (PET/CT) studies in U87 tumor models, which showed only modest tumor uptake and retention, owing to rapid excretion. These results demonstrate that the novel click RGD mimics are excellent radiolabeled probes for in vitro and cell-based studies on αvβ3 integrin, whereas further optimization of their pharmacokinetic and dynamic profiles is necessary for successful use in in vivo imaging.
Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action
Olson, Richard E.,Sielecki, Thais M.,Wityak, John,Pinto, Donald J.,Batt, Douglas G.,Frietze, William E.,Liu, Jie,Tobin, A. Ewa,Orwat, Michael J.,Di Meo, Susan V.,Houghton, Gregory C.,Lalka, George K.,Mousa, Shaker A.,Racanelli, Adrienne L.,Hausner, Elizabeth A.,Kapil, Ram P.,Rabel, Shelley R.,Thoolen, Martin J.,Reilly, Thomas M.,Anderson, Paul S.,Wexler, Ruth R.
, p. 1178 - 1192 (2007/10/03)
Modification of the α-carbamate substituent of isoxazoline GPIIb/IIIa (α(IIb)β3) antagonist DMP 754 (7) led to a series of α-sulfonamide and α-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-α- sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)- diaminopropionate stereochemistry, were found to impact a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.
Non-peptide GPIIb/IIIa inhibitors. 20. Centrally constrained thienothiophene α-sulfonamides are potent, long acting in vivo inhibitors of platelet aggregation
Egbertson, Melissa S.,Cook, Jacquelynn J.,Bednar, Bohumil,Prugh, John D.,Bednar, Rodney A.,Gaul, Stanley L.,Gould, Robert J.,Hartman, George D.,Homnick, Carl F.,Holahan, Marie A.,Libby, Laura A.,Lynch Jr., Joseph J.,Lynch, Robert J.,Sitko, Gary R.,Stranieri, Maria T.,Vassallo, Laura M.
, p. 2409 - 2421 (2007/10/03)
The synthesis and pharmacology of 4, a potent thienothiophene non- peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion- controlled process (k(on) = 3.3 x 106 M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (K(d) = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 mg/kg, and an oral dose of 50-90 mg/kg followed by low daily doses of 10 mg/kg was sufficient to maintain ~80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 ± 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.
Fibrinogen receptor antagonists
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, (2008/06/13)
Novel fibrinogen receptor antagonists of the formula: are provided in which the claimed compounds exhibit fibrinogen receptor antagonist activity, inhibit platelet aggregation and are therefore useful in modulating thrombus formation.
