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Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban
Author(s) -
Mousa Shaker A,
Bozarth Jeffrey M,
Naik Ulhas P,
Slee Andrew
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703943
Subject(s) - platelet , chemistry , binding site , platelet activation , fibrinogen , platelet glycoprotein gpiib iiia complex , dissociation constant , biochemistry , stereochemistry , receptor , medicine
A number of non‐peptide orally active RGD mimetic prodrug such as Orbofiban, Sibrafiban, SR121566, Roxifiban and others entered into the clinical evaluation stage. Some of these agents were terminated and some are still in clinical trials. The present study examined the platelet GPIIb/IIIa binding profiles for the active form of Roxifiban, Sibrafiban, SR121566 and Orbofiban using 3 H‐Roxifiban active form (XV459), 3 H‐DMP728, 125 I‐Echistatin, and 125 I‐Fibrinogen. Either DMP728, Orbofiban, Sibrafiban, SR121566 or Roxifiban active form as well as other RGD mimetic bind to the same binding site (s) on human platelets as evident from the competitive inhibition of binding of each other to human platelet. Additionally, Roxifiban active form competed with FITC labeled GPIIb/IIIa antagonist cyclic RGD peptidomimetic (XL086) as demonstrated using confocal microscopy technique. Roxifiban active form (XV459) demonstrated the highest potency in inhibiting 3 H‐XV459, 3 H‐DMP728, 125 I‐Echistatin, and 125 I‐Fibrinogen binding to human platelets as compared to the others. Structure activity relationship within the isoxazoline Roxifiban series showed that substituent at the α‐carbon next to the carboxy terminal represents an exosite for the affinity binding to human platelets leading to slow platelet dissociation rate. These data indicated a distinct binding profile for Roxifiban (high affinity to both activated and resting platelets associated with a relatively slow K off ) as compared to others. These differences might determine the pharmacodynamics and pharmackokinetics of the different GPIIb/IIIa antagonists.British Journal of Pharmacology (2001) 133 , 331–336; doi: 10.1038/sj.bjp.0703943