PMID: 11312916Apr 21, 2001Paper

Discovery of an orally active non-peptide fibrinogen receptor antagonist based on the hydantoin scaffold

Journal of Medicinal Chemistry
H U StilzG Zoller

Abstract

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with K(i) values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.

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Citations

Jun 15, 2005·Bioorganic & Medicinal Chemistry·Jason J ChrumaRonald Breslow
Aug 2, 2006·Bioscience, Biotechnology, and Biochemistry·Junichi ManoSakayu Shimizu
Sep 11, 2004·Biochemical and Biophysical Research Communications·M S AguzziA Facchiano
Jun 15, 2007·Chemistry : a European Journal·Carsten SchmuckThomas Schrader
Oct 19, 2012·Organic & Biomolecular Chemistry·Francesca OlimpieriAlessandro Volonterio
Sep 25, 2003·British Journal of Pharmacology·N B DassG J Sanger
Feb 6, 2007·Magnetic Resonance in Chemistry : MRC·Mary M SeniorAndrew Stamford
Jan 10, 2019·European Journal of Medicinal Chemistry·SeoHyun ChoDongyun Shin
Feb 19, 2021·The Journal of Organic Chemistry·Ponnusamy Pon SathieshkumarRajagopal Nagarajan
May 14, 2008·Journal of the American Chemical Society·Baoguo ZhaoYian Shi
Jun 21, 2002·Organic Letters·Stephan Rensing, Thomas Schrader
Feb 8, 2002·Journal of Combinatorial Chemistry·Marie LamotheMichel Perez
Aug 21, 2013·Journal of the American Chemical Society·Keisuke TomoharaTakeo Kawabata
Apr 23, 2019·ACS Combinatorial Science·Oleksandr VyhivskyiElena K Beloglazkina
Aug 19, 2007·The Journal of Organic Chemistry·Alicia BotoRosendo Hernández
Apr 6, 2006·Journal of the American Chemical Society·Wei ChenMichael K Gilson

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