4352 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
Communications to the Editor
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Ru, Y.; Bacheler, L. T.; Meek. J . L.; Otto, M. J .; Rayner, M. M.;
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able, Non-peptide Cyclic Urea as HIV Protease Inhibitors.
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SC-55389a presented at Session 46 (I) at the 34th ICAAC,
Orlando, FL, 1994.
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in Complex with VX-478, a Potent and Orally Bioavailable
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and Resistance Studies of AG1343, an Orally Bioavailable
Inhibitor of Human Immunodeficiency Virus Protease. Antimi-
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Akaju, K.; Kiso, Y. Kynostatin KNI-227 and -272, Highly Potent
Anti-HIV Agents: Conformationally Constrained Tripeptide
Inhibitors of HIV Protease Containing Allophenylnorstatine.
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(20) Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K.-
T.; Howe, W. J .; Yang, C.-P.; Strohbach, J . W.; Turner, S. R.;
McGrath, J . P.; Bohanon, M. J .; Lynn, J . C.; Mulichak, A. M.;
Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J .; Moon, J . B.;
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R. J .; Schwende, F. J .; Howard, G. M.; Padbury, G. E.; Toth, L.
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Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-
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L. A.; McGrath, J . P.; Lynn, J . C.; Horng, M.-M.; Hinshaw, R.
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Padbury, G. E.; Dalga, R. J .; Shiou, L.; Possert, P. I.; Rush, B.
D.; Wilkinson, K. F.; Howard, G. M.; Toth, L. N.; Williams, M.
G.; Kakuk, T. J .; Cole, S. L.; Zaya, R. M.; Thaisrivongs, S.;
Aristoff, P. A. Structure-Based Design of Sulfonamide Substi-
tuted Non-peptidic HIV Protease Inhibitors. J . Med. Chem. 1995,
38, 4968-4971.
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Anticoagulant, Warfarin, on HIV-1 Replication and Spread.
AIDS 1993, 7, 129-130.
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Inhibition of HIV-1 Protease by 4-Hydroxy-benzopyran-2-ones
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F.; Dunbar, J . B., J r.; Ferguson, D.; Tummino, P. J .; Hupe, D.;
Tait, B. D.; Domagala, J . M.; Humblet, C.; Bhat, T. N.; Liu, B.;
Guerin, D. M. A.; Baldwin, E. T.; Erickson, J . W.; Sawyer, T. K.
Novel Series of Achiral, Low Molecular Weight, and Potent
HIV-1 Protease Inhibitors. J . Am. Chem. Soc. 1994, 116, 6989-
6990.
(26) Lunney, E. A.; Hagen, S. E.; Domagala, J . M.; Humblet, C.;
Kosinski, J .; Tait, B. D.; Warmus, J . S.; Wilson, M.; Ferguson,
D.; Hupe, D.; Tummino, P. J .; Baldwin, E. T.; Bhat, T. N.; Liu,
B.; Erickson, J . W. A Novel Nonpeptide HIV-1 Protease Inhibi-
tor: Elucidation of the Binding Mode and Its Application in the
Design of Related Analogs. J . Med. Chem. 1994, 37, 2664-2677.
(27) Wlodawer, A.; Erickson, J . W. Structure-based Inhibitors of
HIV-1 Protease. Annu. Rev. Biochem. 1993, 62, 543-585.
(28) Appelt, K. Crystal Structures of HIV-1 Protease-Inhibitor Com-
plexes. Perspect. Drug Discovery Des. 1993, 1, 23-48.
(29) Hamilton, H. W.; Tait, B. D.; Gajda, C.; Hagen, S. E.; Ferguson,
D.; Lunney, E. A.; Pavlovsky, A.; Tummino, P. J . 6-Phenyl-
6-alkylamido-5,6-dihydro-2H-pyran-2-ones: Novel HIV Protease
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cated only a 2-3-fold increase in IC90 value for
U-140690.40
After 5 mg/kg intravenous dosing to rats, CLtot ) 0.17
( 0.10 (L/h)/kg, Vss ) 0.51 ( 0.14 L/kg, and t1/2 ) 5.4 (
0.3 h. After 10 mg/kg oral dosing to rats, F ) 30%
(relative to the 5 mg/kg intravenous dosing). Time-
course blood levels of U-140690 after iv and po dosings
in rats are shown in Figure 3. Importantly, the blood
levels of U-140690 exceeded 1 µM (the in vitro IC90 value
in the presence of 10% fetal bovine serum and 75%
human plasma) for 8-12 h. Additional extensive pre-
clinical and safety studies are underway in order to
initiate clinical trials of U-140690 as the third-genera-
tion development candidate for the treatment of HIV
infection.
Su p p or tin g In for m a tion Ava ila ble: Physical data for
compounds 7, 8, VIIa , VIIb, VIIc, and VIId ; descriptions of
the HIV protease inhibition and cell-culture antiviral assays;
crystallization procedure for the recombinant triple mutant
of HIV-1 protease (Q7K/L33I/L63I) complexed with compounds
V and VIIb; data collection and structure refinement descrip-
tion and a table summary of selected diffraction data collection
and refinement statistics for the two crystal structures (7
pages). Ordering information is given on any current mast-
head page.
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