De novo design, discovery and development of cyclic urea HIV protease inhibitors

From new simple aliphatic to aromatic heterocycles built from 2-chloroethylisocyanate

“…Once intermediate XIII is formed (path B), it releases HCl to give XIV and CO leading to the very reactive intermediates XV, from where the pyrazine heterocycle can be formed through XVI-XVIII. Desorption of this structure explains the formation of the radical hydro-1,4-pyrazine (30) which, for instance, could recombine with radical 23 allowing the formation of the other pyrazines (19)(20)(21)(22) after the loss of chlorine and hydrogen abstraction (Scheme 4).…”

P‐Glycoprotein Effects of Cyclic Urea HIV Protease Inhibitor DMP 323 in Competitional Absorption Studies

“…A so far disappointing class has been that of the cyclic ureas with maintaining bioavailability problems [13]. Since also structurally improved derivatives showed only unsatisfying oral absorption rates, we decided to investigate the reasons for this behaviour with one of the early representatives DMP 323 (Fig.…”

First Bioanalytical Evaluation of Nonpeptidic Cage Dimeric HIV-1 Protease InhibitorN-Benzyl 4-Aryl-1,4-dihydropyridine H17: Biotransformation and Toxicity on Hep G2 Cells

“…From the series of cyclic ureas the most potent representatives DMP 323 and DMP 450 failed in clinical trials because of a disappointing bioavailability [4] . While DMP 323 showed poor absorption and extensive oxidative metabolism of the hydroxymethylene groups [4,5] , the therapeutically necessary blood levels of DMP 450 were not achieved because of high plasma protein binding [4] .…”