Integrin inhibitors

Thiocarbamate derivatives, (VI), effective as a4 integrin inhibitors having enhanced resistant to metabolism were prepared by Jackson (6) and used in treating diseases mediated by the binding interaction of a4 integrin such as inflammatory disorders. 

G. Holzemann etal, US Patent 6,649,613 (November 18, 2003) Assignee Merek Patent GmbH Utility Integrin Inhibitors... 

Stupp, R., Ruegg, C. Integrin inhibitors reaching the clinic. J. Clin. Oncol. 2007,25,1637-1638. 

Acute cholestatic hepatitis with hepatic failure occurred in 48-year-old patient with a glioblastoma taking long-term valproate when temozolomide and the integrin inhibitor cilengitide were added [379" ]. Valproate was withdrawn and the liver tests normalized. 

Tucker GC. av-Integrin inhibitors and cancer therapy. Curr. Opin. Invest. Drugs 2003 4 722-731. 

A 3D model of the fibrinogen-derived (very late antigen-4, VLA-4) inhibitor 4-[N -(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val was derived from the X-ray structure of the related integrin-binding region of the vascular cell adhesion molecule-1 (VCAM-1). A 3D pharmacophore was generated with the program Catalyst, and a 3D search was performed in 8624 molecules from... 

Catalyst was also used by Singh et al. for the identification of potent and novel integrin a4/Sl antagonists [294]. The authors describe a series of potent inhibitors of a4 81 that were discovered using pharmacophore-based virtual screening for replacements of the peptide region of an existing tetrapeptide-based inhibitor derived from fibronectin. 

In addition to the inhibitors of integrins and their ligands, research is also ongoing to find... 

Gordon C, Tucker GC. Inhibitors of integrins. Curr Opin Pharmacol 2002 2 394-402. 

Dutta AS, Gormley JJ, Coath M, et al. Potent cyclic peptide inhibitors of VLA-4 (a4 pi Integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation. 7 Pept Sci 2000 6 398-412. 

PC3 Prostate Invasive (EMT) phenotype developed STAT/interferon, P13-kinase, AKT, and integrin signaling PI3-kinase inhibitors blocked invasive cell growth more effectively in 3-D (30)... 

R. Haubner, D. Finsinger, H. Kessler, Stereoisomeric peptide libraries and peptido-mimetics for designing selective inhibitors of the alpha-v-beta-3 integrin for a new cancer therapy, Angew. Chem. Int. Ed. Engl. (1997) 1374-1389. 

Chadderdon, R.C. and Cappello, M. (1999) The hookworm platelet inhibitor functional blockade of integrins GPIIb/llla (alphallbbeta3) and GPIa/lla (alpha2beta1) inhibits platelet aggregation and adhesion in vitro. Journal of Infectious Diseases 179, 1235-1241. 

During the course of this work it was also found that simple treatment of the carbamate condensation product 65 with 1 M KOH gave the corresponding hydantoin, 68. Reports of the biological utility of cyclic ureas and hydantoins have appeared in several areas, including applications as inhibitors of integrins and kinases.35 Representative examples of each core, 69 through 76, with isolated yields are shown in Fig. 6. 

Blockers/inhibitors of platelets receptors GP Ilb/IIIa (integrin allb(33) (abeiximab, tirofiban, eptifibatide) Prevent the link of fibrinogen with platelet receptors inhibiting platelet aggregation in front of different agonists... 

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