Joachim Gante

Prodrug Approach for αΙΙbβ3-Peptidomimetic Antagonists to Enhance Their Transport in Monolayers of a Human Intestinal Cell Line (Caco-2): Comparison of In Vitro and In Vivo Data

AbstractPurpose. Different lipophilic derivatives of a potent αΙΙbβ3- antagonist with benzamidino-oxazolidinone structure were investigated with respect to transport and metabolism properties to evaluate their potential as prodrugs with improved absorption behavior. Methods. Intestinal transport and metabolism of the compounds were studied in Caco-2 monolayers under in vitro conditions and quantitated by a reversed-phase HPLC- method. Peroral bioavailability in cynomolgus monkeys and inhibition of platelet aggregation (guinea pig) were compared to in vitro permeability coefficients. Results. N-alkoxycarbonyl- and N-benzoyl- derivatization of the benzamidine-parent drug increased the apparent permeabilities across Caco-2 monolayers by a factor of 25-100 fold. Most prodrugs were transported mainly by passive diffusion, whereas the methoxycarbonyl-derivative EMD 122347 displayed directional transport from basolateral (BL) to apical (AP). This polarized efflux was concentration dependent (saturable kinetics with Km = 207 μM, Vmax = 0.275 nmol cm-2 min-1) and could be reduced in the presence of verapamil (300 μM), an inhibitor of p-glycoprotein. Cell mediated cleavage of the prodrugs was low and showed only slight differences to hydrolysis in buffer solution, indicating a predominantly non enzymatic cleavage. Both peroral bioavailability (monkey) and the inhibition of ex-vivo platelet aggregation (guinea pig) gave the same rank order as the permeability coefficients obtained in Caco-2 monolayers. Conclusions. Alkoxycarbonylamidine- and benzoylamidine promoieties of a RGD mimetic αΙΙbβ3-antagonist considerably increased both effect bioavailabilities in animal experiments as well as in-vitro permeability in cell monolayers, demonstrating the potential of this approach to enhance transport of peptidomimetic drugs.

Synthesis of a new dipeptide-type 5,1-benzothiazocine system

Abstract The synthesis of a new biologically active 5,1-benzothiazocine systemis described.