BMS-207940, a potent endothelin receptor antagonist, exists as rapidly interconverting atropisomers. The plasma interconversion t(1/2) is approximately 2.5 hours at 400 microg/mL under room temperature and decreases to < 0.1 hours at 20 microg/mL, making it extremely difficult to conduct pharmacokinetic studies of individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940 in humans were reasonably described by a one-compartmental model with an apparent terminal elimination t(1/2) of 15 hours. Given the above rates, simulations were conducted based on a one-compartmental model to explore the possible range of individual rates of atropisomer elimination and potential difference in plasma exposure to the two atropisomers. Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and between 0.046 and 0.092 h(-1), respectively. The estimation of the upper bounds for atropisomer elimination rate constants is robust and relatively insensitive to the rate of atropisomer interconversion compared to the rate of racemate elimination. Simulations of the administration of a single atropisomer or the 50/50 racemate, based on all the possible scenarios of individual atropisomer elimination, showed little difference in plasma exposure to the two atropisomers. Potential differences in plasma exposure to the two atropisomers depend, to a larger extent, on the ratio of the rate of atropisomer interconversion versus racemate elimination and, to a lesser extent, on the conformation of atropisomers administered. When atropisomer interconversion is 10-fold or more rapid than racemate elimination, the largest possible difference in plasma exposure between the two atropisomers is below 20%, regardless of the route and conformation of the atropisomer(s) administered.

In this paper, a series of novel derivatives of camptothecin substituted norcantharimide was designed by mimic strategy. These compounds were synthesized in moderate yields by directly coupling CPT with N-amino acid norcantharimides. Their cytotoxicity to four human tumor cell lines (HepG2, BGC-803, SW480 and PANC-1) and normal human cell lines L-O2 and HIEC was evaluated. The synthesized CPT substituted norcantharimide analogs (3g and 3f) showed better anti-hepatocarcinoma activity than CPT. Compounds 3d, 3e, 3g, 3h and 3i also showed strong inhibition activity against BGC803.

in Wiley Online Library (wileyonlinelibrary.com).4-Methylimidazole-2-carboxylic acid was synthesized from 4-methylimidazole with a total yield of 65% over four steps including an N-benzyl protection, acylation, debenzylation, and ester hydrolysis. The solvent, base, temperature, and reaction time are optimized for this method. This efficient, convenient, and low-cost protocol uses inexpensive reagents in each step to obtain 4-methylimidazole-2-carboxylic acid in high yield.Ethyl 4-methyl-1H-imidazole-2-carboxylate V. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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