Orally Active Isoxazoline Glycoprotein IIb/IIIa Antagonists with Extended Duration of Action

Abstract

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.

Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban

“…The difference in platelet dissociation rate appears to be responsible for the duration of in vivo antiplatelet efficacy. XR299 demonstrated sustained antiplatelet efficacy when given three times a day in canine platelets ( Mousa et al ., 1998d ), Roxifiban when given QD in baboon platelets ( Mousa et al ., 1998b ), and DMP802 when given once a week in baboon platelets ( Mousa et al ., 1998e ; Olson et al ., 1997 ). Roxifiban active form demonstrated high potency in inhibiting platelet aggregation.…”

“…Roxifiban, an α‐carbamate substituted isoxazoline analogue demonstrated tight binding and slow dissociation rate from human platelet ( Mousa et al ., 1998a ) as compared to non‐α carbon substituted analogue, XR299 ( Mousa & Wityak, 1998 ; Wityak et al ., 1997 ). Furthermore, α‐substitution with sulfonamide resulted in an even slower platelet dissociation rate ( Olson et al ., 1997 ). Structure activity relationship within the isoxazoline Roxifiban series showed that substituent at the α‐carbon next to the carboxy terminal represent an exosite for the tight binding to human platelets leading to slow platelet dissociation rate ( Mousa & Wityak, 1998 ; Xue et al ., 1997 ).…”

“…125 I‐Echistatin was obtained from Amersham Pharmacia Biotech Inc. (Piscataway, NJ, U.S.A.). All free acid forms of Roxifiban, other isoxazoline analogues (XR299, DMP802 and XV454), and other GPIIb/IIIa antagonists radiolabeled form were synthesized at DuPont Pharmaceuticals, (Wilmington, DE, U.S.A.) ( Mousa and Wityak, 1998 ; Olson et al ., 1997 ; Wityak et al ., 1997 ; Xue et al ., 1997 ). FITC‐labelled cyclic RGD (XL086) was synthesized at DuPont Pharmaceuticals Co. (Wilmington, DE, U.S.A.).…”

Photochemistry of 2-Nitroarenes: 2-Nitrophenyl-α-trifluoromethyl Carbinols as Synthons for Fluoroorganics

“…More intriguingly, changing the solvent to acetonitrile led to the formation of 2-trifluoroacetyl nitrosoarenes and their hydrates as the major products. Molecules containing the isoxazoline core are found to exhibit significant antiplatelet activity. , These types of molecules also exhibit insecticidal properties; Afoxolaner and Fluralaner are commercial drugs used to treat fleas in mammals (Scheme ). , Nitroso compounds serve as reactants for various synthetic transformations such as those involving nitroso aldol reactions, − ene reactions, cycloaddition, etc .…”

Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia

“…13 For all in vitro studies, XP280, the salt of the active, free acid form of the prodrug roxifiban was employed. 19 …”