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

Abstract

Cyclic ureas form a perspective class of non-peptidic HIV-1 protease inhibitors with major bioavailability problems. Low absorption rates of DMP 323 as one of the first representatives led to investigations whether transport efflux pump P-glycoprotein (P-gp) within the intestine may be partly responsible for the low absorption rates. DMP 323 proved to be a P-gp substrate in competition studies with P-gp inhibitor ritonavir and H17 as a representative of another class of non-peptidic HIV-1 protease inhibitors. Intestinal DMP 323 absorption was mainly increased under co-application of both ritonavir and H17. DMP 323 used as a membrane efflux pump inhibitor itself showed little affinities to P-gp compared to H17 as strong P-gp inhibitor. So P-gp proved to play a decisive role in the low intestinal absorption of the cyclic urea representative DMP 323.

Construction of 3,12-Diazatetracyclododecane-dienes through Unexpected Visible-Light-Induced Radical Cascade Cyclization

“…As common and important nitrogen-containing heterocyclic structural units, 1,4-dihydropyridines (1,4-DHPs) are present in many biologically active natural and synthetic products . In addition to being used as calcium antagonists and antimicrobial agents, they are also important intermediates for the preparation of cage compounds that have been tested as HIV-1 protease inhibitors …”

Effects of Structural Symmetry on NMR Spectra of 3,9-Diazatetraasteranes

“…The tetraasterane was synthesized by a dimerization of 1,4cyclohexadiene derivatives, while the 3,9-diazatetraasterane was aza-analogous of tetraasterane and synthesized by a dimerization of 1,4-dihydropyridine derivatives [4][5][6]. With a C 2 symmetric property, the C 2 -3,9-diazatetraasteranes was synthesized via the self-dimerization of the 1,4-dihydropyridines, which exhibited anti-HIV-1 protease activity, anti-tumor activities, modulating multidrug resistance (MDR) towards P-glycoprotein, and other physiological and pharmacological activities [7][8][9][10][11][12]. While non-C 2 -3,9diazatetraasteranes was synthesized via the cross-dimerization of different 1,4-dihydropyridines [13].…”