“…8 Several orally active nonpeptide GPIIb/IIIa antagonists ( Figure 1) are in advanced stages of clinical evaluation. [9][10][11][12][13][14][15] Results from clinical trials of GPIIb/IIIa antagonists suggest that substantial inhibition of platelet aggregation may be achieved without unduly compromising hemostasis and that GPIIb/IIIa blockade may lower the risk of thrombotic events in the context of unstable angina and following coronary angioplasty. 16- 18 We recently reported that isoxazolinylacetamides of -alanine are highly effective frameworks for the display of the basic and acidic functionality requisite to high GPIIb/IIIa affinity 19 and that the R-carbamate diaminopropionate 1 (DMP 754) [20][21][22] provides high oral potency and prolonged antiplatelet effects in dogs as compared to the R-unsubstituted analogue 2 (XR300).…”
Section: Introductionmentioning
confidence: 99%
“…Such agents feature appropriately oriented Arg-guanidine mimics and carboxylate groups appended to a variety of peptidic and nonpeptidic core structures. , Peptide and peptidomimetic antagonists of GPIIb/IIIa have been shown to effectively block in vitro or ex vivo platelet aggregation as well as arterial thrombosis in various animal models . Several orally active nonpeptide GPIIb/IIIa antagonists (Figure ) are in advanced stages of clinical evaluation. − Results from clinical trials of GPIIb/IIIa antagonists suggest that substantial inhibition of platelet aggregation may be achieved without unduly compromising hemostasis and that GPIIb/IIIa blockade may lower the risk of thrombotic events in the context of unstable angina and following coronary angioplasty. − 1 Representative oral nonpeptide GPIIb/IIIa antagonists in clinical development.…”
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart 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.
“…8 Several orally active nonpeptide GPIIb/IIIa antagonists ( Figure 1) are in advanced stages of clinical evaluation. [9][10][11][12][13][14][15] Results from clinical trials of GPIIb/IIIa antagonists suggest that substantial inhibition of platelet aggregation may be achieved without unduly compromising hemostasis and that GPIIb/IIIa blockade may lower the risk of thrombotic events in the context of unstable angina and following coronary angioplasty. 16- 18 We recently reported that isoxazolinylacetamides of -alanine are highly effective frameworks for the display of the basic and acidic functionality requisite to high GPIIb/IIIa affinity 19 and that the R-carbamate diaminopropionate 1 (DMP 754) [20][21][22] provides high oral potency and prolonged antiplatelet effects in dogs as compared to the R-unsubstituted analogue 2 (XR300).…”
Section: Introductionmentioning
confidence: 99%
“…Such agents feature appropriately oriented Arg-guanidine mimics and carboxylate groups appended to a variety of peptidic and nonpeptidic core structures. , Peptide and peptidomimetic antagonists of GPIIb/IIIa have been shown to effectively block in vitro or ex vivo platelet aggregation as well as arterial thrombosis in various animal models . Several orally active nonpeptide GPIIb/IIIa antagonists (Figure ) are in advanced stages of clinical evaluation. − Results from clinical trials of GPIIb/IIIa antagonists suggest that substantial inhibition of platelet aggregation may be achieved without unduly compromising hemostasis and that GPIIb/IIIa blockade may lower the risk of thrombotic events in the context of unstable angina and following coronary angioplasty. − 1 Representative oral nonpeptide GPIIb/IIIa antagonists in clinical development.…”
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart 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.
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