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Chemical Compound Review

CHEMBL81396     3-[[(4R,5S,6S,7R)-4,7- dibenzyl-3-[[3...

Synonyms: AC1LA9HU, 152928-65-9
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Disease relevance of AIDS-042906

  • We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit [1].
  • CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals [2].
  • Inhibitory effect of a cyclic urea derivative on rubella virus replication [3].

High impact information on AIDS-042906

  • In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability [2].
  • Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors [2].
  • The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation [2].
  • The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants [4].
  • Three-dimensional quantitative structure-activity relationship study on cyclic urea derivatives as HIV-1 protease inhibitors: application of comparative molecular field analysis [5].

Chemical compound and disease context of AIDS-042906

  • X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule [6].
  • Utilizing this system we studied the fate of mixtures of wild-type and the protease-resistant mutant variant I84V in the presence and absence of the cyclic urea HIV protease inhibitor, DMP 450 [7].
  • Four different HIV protease inhibitors were tested including P9941, a C2 symmetrical diol (Du Pont-Merck); A80987, an asymmetric mono-ol (Abbott); XM323, a cyclic urea (Du Pont-Merck); and Ro31-8959, an asymmetric hydroxyethylene isostere (Roche) [8].
  • A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir [9].
  • The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease [9].

Biological context of AIDS-042906


Associations of AIDS-042906 with other chemical compounds


Gene context of AIDS-042906


Analytical, diagnostic and therapeutic context of AIDS-042906


  1. Molecular recognition of cyclic urea HIV-1 protease inhibitors. Ala, P.J., DeLoskey, R.J., Huston, E.E., Jadhav, P.K., Lam, P.Y., Eyermann, C.J., Hodge, C.N., Schadt, M.C., Lewandowski, F.A., Weber, P.C., McCabe, D.D., Duke, J.L., Chang, C.H. J. Biol. Chem. (1998) [Pubmed]
  2. Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors. Rodgers, J.D., Lam, P.Y., Johnson, B.L., Wang, H., Li, R., Ru, Y., Ko, S.S., Seitz, S.P., Trainor, G.L., Anderson, P.S., Klabe, R.M., Bacheler, L.T., Cordova, B., Garber, S., Reid, C., Wright, M.R., Chang, C.H., Erickson-Viitanen, S. Chem. Biol. (1998) [Pubmed]
  3. Inhibitory effect of a cyclic urea derivative on rubella virus replication. Galabov, A.S., Mihneva, Z., Hadjiathanassova, V., Zhukovec, V. Z. Naturforsch., C, J. Biosci. (2000) [Pubmed]
  4. Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Hodge, C.N., Aldrich, P.E., Bacheler, L.T., Chang, C.H., Eyermann, C.J., Garber, S., Grubb, M., Jackson, D.A., Jadhav, P.K., Korant, B., Lam, P.Y., Maurin, M.B., Meek, J.L., Otto, M.J., Rayner, M.M., Reid, C., Sharpe, T.R., Shum, L., Winslow, D.L., Erickson-Viitanen, S. Chem. Biol. (1996) [Pubmed]
  5. Three-dimensional quantitative structure-activity relationship study on cyclic urea derivatives as HIV-1 protease inhibitors: application of comparative molecular field analysis. Debnath, A.K. J. Med. Chem. (1999) [Pubmed]
  6. Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies. Jadhav, P.K., Woerner, F.J., Lam, P.Y., Hodge, C.N., Eyermann, C.J., Man, H.W., Daneker, W.F., Bacheler, L.T., Rayner, M.M., Meek, J.L., Erickson-Viitanen, S., Jackson, D.A., Calabrese, J.C., Schadt, M., Chang, C.H. J. Med. Chem. (1998) [Pubmed]
  7. Population dynamics studies of wild-type and drug-resistant mutant HIV in mixed infections. Rayner, M.M., Cordova, B., Jackson, D.A. Virology (1997) [Pubmed]
  8. Limited sequence diversity of the HIV type 1 protease gene from clinical isolates and in vitro susceptibility to HIV protease inhibitors. Winslow, D.L., Stack, S., King, R., Scarnati, H., Bincsik, A., Otto, M.J. AIDS Res. Hum. Retroviruses (1995) [Pubmed]
  9. Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV. Flosi, W.J., Degoey, D.A., Grampovnik, D.J., Chen, H.J., Klein, L.L., Dekhtyar, T., Masse, S., Marsh, K.C., Mo, H.M., Kempf, D. Bioorg. Med. Chem. (2006) [Pubmed]
  10. Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors. Ala, P.J., Huston, E.E., Klabe, R.M., McCabe, D.D., Duke, J.L., Rizzo, C.J., Korant, B.D., DeLoskey, R.J., Lam, P.Y., Hodge, C.N., Chang, C.H. Biochemistry (1997) [Pubmed]
  11. Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors. A 3D-QSAR-CoMFA method for new antiviral drug design. Avram, S., Svab, I., Bologa, C., Flonta, M.L. J. Cell. Mol. Med. (2003) [Pubmed]
  12. P-Glycoprotein Effects of Cyclic Urea HIV Protease Inhibitor DMP 323 in Competitional Absorption Studies. Richter, M., Gy??m??nt, N., Moln??r, J., Hilgeroth, A. Arch. Pharm. (Weinheim) (2006) [Pubmed]
  13. Cyclic urea nucleosides. Cytidine deaminase activity as a function of aglycon ring size. Liu, P.S., Marquez, V.E., Driscoll, J.S., Fuller, R.W., McCormack, J.J. J. Med. Chem. (1981) [Pubmed]
  14. Isolation and chemistry of the mixed anhydride intermediate in the reaction catalyzed by dethiobiotin synthetase. Gibson, K.J. Biochemistry (1997) [Pubmed]
  15. Topical mosquito repellents XII: N-substituted ureas and cyclic ureas. Skinner, W.A., Crawford, H.T., Rutledge, L.C., Moussa, M.A. Journal of pharmaceutical sciences. (1979) [Pubmed]
  16. Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions. Shue, H.J., Chen, X., Schwerdt, J.H., Paliwal, S., Blythin, D.J., Lin, L., Gu, D., Wang, C., Reichard, G.A., Wang, H., Piwinski, J.J., Duffy, R.A., Lachowicz, J.E., Coffin, V.L., Nomeir, A.A., Morgan, C.A., Varty, G.B., Shih, N.Y. Bioorg. Med. Chem. Lett. (2006) [Pubmed]
  17. Human immunodeficiency virus type 1 proteinase resistance to symmetric cyclic urea inhibitor analogs. Nillroth, U., Vrang, L., Markgren, P.O., Hultén, J., Hallberg, A., Danielson, U.H. Antimicrob. Agents Chemother. (1997) [Pubmed]
  18. Computer-aided design of artificial enzymes: cyclic urea mimetics of alpha-chymotrypsin. Venanzi, C.A., Bunce, J.D. Enzyme (1986) [Pubmed]
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