Fibrinogen receptor antagonists

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

Ku TW, Miller WH, Bondinell WE, Erhard KF, Keenan RM, Nichols AJ, Peishoff CE, Samanen JM, Wong AS, Huffman WF. Potent non-peptide fibrinogen receptor antagonists which present an alternative pharmacophore. J Med Chem 1995 38 9-12. 

A good example of this is the work completed on the fibrinogen receptor antagonist L-767,679 [10]. This compound exhibits extreme polarity due to its zwitter-... 

Fig. 3.11 Structures of the fibrinogen receptor antagonist L-767,679 and its benzyl ester (L-775,318) analogue.

An in vitro or ex vivo measure of drug effect, for example, mean inhibitory concentration (MIC) of an antimicrobial against bacterial culture inhibition of ADP-induced platelet aggregation with a fibrinogen receptor antagonist. 

Benzylacetoacetate (5) was reduced to be n z y I - (.S ) - (+) - 3 - h y dm x y b u ty rale (6) by the yeast Candida schatavii MY 1831 (Scheme 19.7), which is considered a possible intermediate in the synthesis of L-734,217 (7), an experimental fibrinogen receptor antagonist.80 Initially, 8 microorganisms were tested for their reduction ability using 5 as substrate. The best culture, C. schatavii MY 1831, yielded product with an ee of 93% and an estimated conversion yield of >95% (by thin layer chromatography [TLC]). 

Bostwick JS, Kasiewski CJ, Chu V et al. (1996) Anti-thrombotic activity of RG13965, a novel platelet fibrinogen receptor antagonist. Thrombosis Research 82 495-507... 

Matsuo O, Rijken DC, Collen D (1981) Thrombolysis by human tissue plasminogen activator and urokinase in rabbits with experimental pulmonary embolus. Nature 291 590-591 Nicolini FA, Lee P, Rios G et al. (1994) Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis. Circulation 89 1802-1809... 

An example of the use of peptidic information comes from the work of Pickett et al. (76) using the known tripeptide RGD (Arg-Gly-Asp) (see Fig. 5.11) motif fibrinogen uses for receptor binding (86). A database of 100,000 compounds, which had been seeded with fibrinogen receptor antagonists covering a wide range of structural classes (see Fig. 5.12), was... 

Bray ML, Janhansouz H, Kaufman MJ. Selection of optimal hydrale/solvale forms of a fibrinogen receptor antagonist for solid dosage development. Pharm Dev Tech 1999 4 81-87. 

Fibrinogen Receptor Antagonists Design and Clinical Applications... 

BIOLOGICAL TEST SYSTEMS FOR FIBRINOGEN RECEPTOR ANTAGONISTS 38 In vitro assays 38... 

The concept of a fibrinogen receptor antagonist as a powerful new antithrombotic mechanism arose from consideration of the central role of the platelet in thrombosis (Figure 2.1). This aspect of platelet biology has been reviewed in detail elsewhere [1-5] therefore, only brief details will be presented here. 

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