4897-25-0Relevant articles and documents
Rational design of novel immunosuppressive drugs: Analogues of azathioprine lacking the 6-mercaptopurine substituent retain or have enhanced immunosuppressive effects
Crawford, Duncan J. K.,Maddocks, John L.,Jones, D. Neville,Szawlowski, Paul
, p. 2690 - 2695 (1996)
Clinical use of the immunosuppressive drug azathioprine is limited by potentially serious toxic effects related to depression of bone marrow function. The immunosuppressive and toxic properties of azathioprine are regarded as being properties of the cytotoxicity of its metabolite, 6- mercaptopurine (6-MP). However, azathioprine has an immunosuppressive effect additional to that attributable to 6-MP alone, and we propose that this is associated with an action of the methylnitroimidazolyl substituent. This suggests a route to the rational design of nontoxic immunosuppressants by replacing the 6-MP component of azathioprine with nontoxic thiols. We have synthesized and tested in vitro 24 such analogues, with two being further tested in vivo. In the human mixed lymphocyte reaction, virtually all compounds showed some degree of activity, 10 compounds being more active than azathioprine. In vivo, two compounds were more effective than azathioprine at prolonging graft survival in mice. In an oral toxicity study in male CD1 mice at doses equivalent to those at which azathioprine caused severe bone marrow depression both analogues had no toxic effects. Our results show that the immunosuppressive effects and bone marrow toxicity of azathioprine are not a consequence of release of 6-MP alone, and with appropriate modification can be separated, an approach which may lead to less toxic immunosuppressive drugs.
HETEROCYCLO-SUBSTITUTED IMIDAZOPYRAZINE PROTEIN TYROSINE KINASE INHIBITORS
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Page/Page column 39-40, (2009/06/27)
Novel heterocyclo-substituted imidazopyrazines and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.
Hetaryl imidazoles: A novel dual inhibitors of VEGF receptors I and II
Kiselyov, Alexander S.,Semenova, Marina,Semenov, Victor V.
, p. 1440 - 1444 (2007/10/03)
A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC50 100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.
