Author/Editor     Cesar, Jožko; Šegula, Mojca; Sollner-Dolenc, Marija
Title     Novejše antiagregatorne učinkovine: antagonisti fibrinogenskega GPIIb/IIIa receptorja
Translated title     Novel antiagrregatory drugs: firbrinogen GPIIb/IIIa receptor antagonists
Type     članek
Source     Farm Vestn
Vol. and No.     Letnik 53, št. 3
Publication year     2002
Volume     str. 261-75
Language     slo
Abstract     Cardiovascular diseases are the leading cause of illnesses and death in the developed world. Design of new antithrombotic agents is therefore one of the most challenging fields of medicinal chemistry and pharmacology. While platelet aggregation plays a vital role in primary haemostasis, under pathological conditions it may lead towards an arterial thrombosis that causes myocardial infarction, ischemic stroke, and peripheral artery disease. The final common pathway resulting in platelet aggregation is the binding of fibrinogen to its GPIIb/IIIa (integrin alphaIIb beta3) receptor on the surface of activated platelets. Drugs inhibiting this binding block arterial thrombosis formation regardless the stimulus that activates platelets. Development of the GPIIb/IIIa antagonists is based predominantly on the RGD (Arg-Gly-Asp) amino acids sequence found in many natural ligands. The molecule of the GPIIb/IIIa antagonist must at least contain a cationic centre, an anionic centre, and a template bringing the two into the appropriate spatial position. Three parenteral GPIIb/IIIa antagonists are nowadays being used in the therapy for the management of the acute coronary syndrome, and as an adjunctive therapy to the coronary surgical procedures. The first group of orally active GPIIb/IIIa antagonists has proved to be ineffective mostly due to their inappropriate pharmacokinetic properties. Clinical studies with new, improved peroral agents are being conducted.
Summary     Bolezni srca in ožilja so v razvitem svetu vodilni vzrok obolevnosti in smrtnosti prebivalstva, zato spada razvoj novih antitrombotičnih učinkovin med najaktualnejša področja farmacevtske kemije in farcnakologije. Agregacija trombocitov ima ključno vlogo v primarni hemostazi, v patoloških pogojih pa je odgovorna za razvoj arterijske tromboze, ki povzroča miokardni infarkt, ishemično možgansko kap in periferno arterijsko bolezen. Končna skupna pot agregacije trombocitov je vezava fibrinogena na fibrinogenski GPIIb/IIIa receptor (integrin alfa IIb beta3) na površini aktiviranih trombocitov. Učinkovine, ki preprečujejo to vezavo, lahko zavirajo nastanek tromboze ne glede na dražljaj, ki trombocite aktivira. Razvoj antagonistov GPIIb/IIIa receptorja temelji v glavnem na aminokislinskem RGD (Arg-Gly-Asp) vezavnem zaporedju, s katerim se na receptor vežejo številni naravni ligandi. Molekula antagonista mora vsebovati kationski center, anionski center in vmesni distančnik, ki omogoča pravilno prostorsko razporeditev omenjenih skupin. V terapiji danes uporabljajo tri parenteralne GPIIb/IIIa antagoniste, ki so indicirani za zdravljenje akutnega koronarnega sindroma in ob kirurških posegih na srčnem žilju. Prvi peroralno uporabni antagonisti so se v kliničnih študijah izkazali za neučinkovite, v glavnem zaradi neustrezttih farmakokinetičnih lastnosti. Študije z novimi, izboljšanimi peroralnimi antagonisti pa so v teku.
Descriptors     THROMBOSIS
PLATELET AGGREGATION INHIBITORS
PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX
HEMOSTASIS