193270-06-3Relevant articles and documents
Fluorobenzamidrazone thrombin inhibitors: Influence of fluorine on enhancing oral absorption
Lee, Koo,Jung, Won-Hyuk,Sang, Yeul Hwang,Lee, Sung-Hack
, p. 2483 - 2486 (2007/10/03)
LB30057 (1) is a selective and efficacious oral thrombin inhibitor. Fluorine-substitution on the phenylene ring of the benzamidrazone portion in both compound 1 and its derivatives gave, in many cases, enhanced oral absorption in rats while maintaining the intrinsic potency and selectivity. Compound 2 demonstrated a 3-fold increase in absorption.
Thrombus imaging using technetium-99m-labeled high-potency GPIIb/IIIa receptor antagonists. Chemistry and initial biological studies
Pearson, Daniel A.,Lister-James, John,McBride, William J.,Wilson, David M.,Martel, Lawrence J.,Civitello, Edgar R.,Dean, Richard T.
, p. 1372 - 1382 (2007/10/03)
Platelet-specific compounds which are radiolabeled with γ-emitting radionuclides may be particularly useful for the noninvasive in vivo detection of thrombi. The synthesis of peptides which are potent inhibitors of platelet aggregation and which contain a chelator for the radionuclide technetium-99m are described. The target compounds were designed such that stable, oxotechnetium(V) species could be prepared where the site of metal coordination was well defined. A strategy was employed where the pharmacophore -Arg-Gly-Asp-(RGD), or RGD mimetic, was constrained in a ring which was formed by the S-alkylation of a cysteine residue with an N-terminal chloroacetyl group. Binding affinities were enhanced by the replacement of arginine with the arginine mimetics S-(3-aminopropyl)cysteine and 4- amidinophenylalanine. Further enhancements could be obtained by the synthesis of oligomers which contained two or more rings containing receptor binding regions. The increase in binding affinity seen was more than that expected from a simple stoichiometric increase of pharmacophore. The most potent compounds described had IC50s of approximately 0.03 μM for the inhibition of human platelet aggregation. Two of the more potent peptides (P280 and P748) were labeled with technetium-99m and assessed in a canine thrombosis model. The 99mTc complexes of the peptides prepared in this work hold promise as thrombus imaging agents due to their high receptor binding affinity, ease of preparation, and expected rapid pharmacokinetics.
Efficient Kg-Scale Synthesis of Thrombin Inhibitor CRC 220
Jendralla, Heiner,Seuring, Bernhard,Herchen, Joerg,Kulitzscher, Bernd,Wunner, Joachim,et al.
, p. 12047 - 12068 (2007/10/02)
Potent thrombin inhibitor 2 is prepared in 10 steps with 20percent overall yield from commercial 4 on a kg-scale by the convergent approach depicted in Schemes 1 and 2.The (R)-configuration of the 4-amidinophenylalanine piperidide moiety is controlled by asymmetric hydrogenation.A novel method, the hydrogenolysis of amidoximes 11 and 21, is employed to attain a particularly clean transformation of the cyano into the amidinium functionality.Despite of the amorphous nature of target compound 2, the approach is devoid of any chromatographic purification.
