Molecular Modelling Analysis of the Metabolism of Anagrelide
Anagrelide is an orally active imidazoquinazoline derivative used for the treatment of thrombocytosis in patients with chronic myeloproliferative disorders. AG is extensively metabolized by the liver into two major metabolites BCH24426 and RL603. AG and its active metabolite RL603 reversibly block the maturation of late-stage megakaryocytes in a dose-dependent manner, thus reducing platelet counts in patients with essential thrombocythaemia. The most common adverse effects associated with anagrelide are headache, palpitations, diarrhoea, asthenia, oedema, nausea, abdominal pain and dizziness. AG is not mutagenic and to date there is no evidence to suggest it is leukaemogenic. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that AG and its metabolites BCH24426 and RL603 have moderately large LUMO-HOMO energy differences so that neither is expected to be highly labile. The active metabolite RL603 has the largest LUMO-HOMO energy difference so that it would be most inert kinetically. Thus although the molecular surfaces of neither AG and its metabolites are found to have some electron-deficient (blue) regions so that they can react with glutathione and nucleobases in DNA, the rates of such adverse reactions are not expected to be significant.
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