A new method for measurement of plasma concentration of orally active glycoprotein IIb/IIIa antagonists

Salyers, Anita K.; Szalony, James A.; Taite, Beatrice B.; Haas, Neal F.; Mehrotra, Devan V.; Feigen, Larry P.; Nicholson, Nancy S.

doi:10.1016/0049-3848(94)90256-9

Cited by 6 publications

(1 citation statement)

References 5 publications

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“…The concentration of the active species in PPP was estimated by a bioassay as described by Salyers et al 38 with modifications. PPP from treated guinea pigs was diluted with PPP from nontreated donor guinea pigs and mixed with PRP from nontreated donors.…”

Section: -Ethynylbenzonitrile (32)mentioning

confidence: 99%

New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antagonists: Orally Active Series of N-Alkylated Amidines with a 6,6-Bicyclic Template

Okumura¹,

Shimazaki²,

Aoki³

et al. 1998

J. Med. Chem.

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The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl [6-[4-(morpholinoformimidoyl)benzamido]-3, 4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S)-4.HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carboxyl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-tetrahydronaphthalene or 3, 4-dihydro-2H-1-benzopyran skeleton showed marked inhibitions with IC50 values of 46-57 nM in human platelet aggregation assay in vitro, but low oral activities. N-Alkylation of the amidino group coupled with the ester prodrug approach afforded MS-180 ((S)-4.HCl), which generates in vivo the corresponding carboxylic acid (S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggregation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 35 nM, respectively) and inhibited the binding of fibrinogen to immobilized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral administration of MS-180 ((S)-4.HCl) to fasted beagle dog, ex vivo inhibition of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selected MS-180 ((S)-4.HCl) as a candidate for clinical evaluation as a drug for the treatment and prevention of thrombosis in patients.

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Section: -Ethynylbenzonitrile (32)mentioning

confidence: 99%