Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase.

1. Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents that are administered concomitantly or sequentially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigated on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enzyme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was determined by measuring the recovery of [14C]5-FU by HPLC. 2. The apparent activity of 5-FU metabolism (2.1-100 microM) showed a linear relationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. Km and Vmax were estimated to be 23 microM and 0.32 nmol min(-1) mg(-1) protein, respectively. Apparent DPD activity for 5-FU (25 microM) in the cytosol from 12 individual donors ranged from 0.017 to 0.39 (0.16 +/- 0.12) nmol min(-1) mg(-1) protein, indicating a large intersubject variance. 3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5-bromouracil (6.3-50 microM), illustrated concentration-dependent inhibition on DPD activity. Isocytosine (6.3-100 microM), used as a negative control, did not affect DPD activity. Bropirimine (6.3-100 microM) also did not show any inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after co-administration of bropirimine with 5-FU prodrugs.

Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.