Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl Ester Prodrugs

Abstract

The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.

Self-assembled nanoparticles based on the c(RGDfk) peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

“…4 Additionally, these carriers have been modified with different targeting ligands, such as the Arg-Glytargeting ability. The RGD peptide and structurally related compounds [9][10][11][12][13][14] are the best-studied ligands that belong to the integrin ligand group. [15][16][17][18] Because these ligands specifically bind to the integrin receptor, which is overexpressed in the endothelial cells of the tumor neovasculature, 19 when applied in vivo, an 8-amino-3,6-dioxaoctanoic acid (PEG)-β-maleimidopropionic acid (MAL) hydrophilically modified, specific integrin αvβ3 receptor-targeted small cyclopeptide c(RGDfk) could lead to the accumulation of siRNA in tumors, resulting in tumor targeting.…”

Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

“…[16][17][18][19] The most studied integrin ligands have been the Arg-Gly-Asp (RGD) motif and structurally related compounds. [20][21][22][23][24][25] The RGD motif can be specifically recognized by integrins α ν β 3 and α ν β 5 which are overexpressed on many solid tumors and in tumor neovasculature, such as in human glioma. 26 Thus, modification of SSL with the RGD motif to achieve targeted drug delivery to tumors and the tumor neovasculature is a promising strategy in the treatment of glioma.…”

Synthesis of RGD amphiphilic cyclic peptide as fibrinogen or fibronectin antagonist

“…However, clinical application of these peptides as thrombosis or metastasis inhibitors is limited by their short half-life in blood. Non-peptide inhibitors of platelet aggregation [6] with a very high in vivo activity [7] and oral activity [8] have been discovered. Moreover, cyclic peptides have been shown to be highly specific of ~tv~3 or ~IIb~3 integrins, depending on their sequence, which induces a specific conformation [9,10].…”