156185-58-9Relevant articles and documents
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.
