Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 1057
tertiary alcohol in the transition-state mimicking scaffold. J. Med.
Chem. 2006, 49, 1828–1832.
(10) Ekegren, J. K.; Gising, J.; Wallberg, H.; Larhed, M.; Samuelsson, B.;
Hallberg, A. Variations of the P2 group in HIV-1 protease inhibitors
containing a tertiary alcohol in the transition-state mimicking scaffold.
Org. Biomol. Chem. 2006, 4, 3040–3043.
alcohol groups. TBAF (3.5–10.0 equiv based on the amount of
starting material 9) in THF was added to the intermediate and stirred
overnight. Purification by flash chromatography gave the corre-
sponding products 12a–c and 12e–s as white solids in yields varying
from 19% to 91%.
General Procedure C for Synthesis of Inhibitors 12t–w.
Palladium-Catalyzed Coupling Reactions. Aryl bromide 13 (1.0
equiv), boronic acid (3.0 equiv), Herrmann’s palladacycle (0.05
equiv), HP(t-Bu)3BF4 (0.10 equiv), K2CO3 (3.0 equiv), DME, and
H2O were added to a 2–5 mL process vial. The mixture was radiated
under microwaves at 120 or 130 °C for 20 min. The mixture was
then extracted with EtOAc, and the organic layer was dried
(MgSO4) and concentrated. TBAF (1.0 M in THF, 10.0 equiv) was
added to the residue and stirred at room temperature overnight.
Water (10 mL) was added to the mixture, followed by extraction
with CH2Cl2, drying (MgSO4), concentration, and purification on
silica to afford the products 12t-w as white solids in 61–80% yield.
{(S)-1-[ N′-[(R)-4-Hydroxy-4-((1S,2R)-2-hydroxy-indan-1-yl-
carbamoyl)-5-phenylpentyl]-N′-(4-pyridin-4-ylbenzyl)hydrazi-
nocarbonyl]-2,2-dimethylpropyl}carbamic Acid Methyl Ester
(12v). The title compound was made according to general procedure
C, using 13 (100.0 mg, 0.1066 mmol), 4-pyridinylboronic acid (39.2
mg, 0.3198 mmol), palladacycle (5.0 mg, 0.0053 mmol), HP(t-
Bu)3BF4 (3.1 mg, 0.0107 mmol), K2CO3 (44.2 mg, 0.3198 mmol),
DME (1.0 mL), and H2O (0.3 mL), which were radiated at 120 °C
for 20 min. TBAF (1.0 M in THF, 1.06 mL, 1.06 mmol) was used
for deprotection. Purification (silica, MeOH/CH2Cl2, 1:99 to 5:95)
(11) Winneroski, L. L.; Xu, Y. Two complementary approaches toward
2-alkoxy carboxylic acid synthesis from 1,3-dioxolan-4-ones. J. Org.
Chem. 2004, 69, 4948–4953.
(12) Bold, G.; Fässler, A.; Capraro, H.-G.; Cozens, R.; Klimkait, T.;
Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.; Tintelnot-
Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.;
Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang,
M. New aza-dipeptide analogues as potent and orally absorbed HIV-1
protease inhibitors: candidates for clinical development. J. Med. Chem.
1998, 41, 3387–3401.
(13) Otteneder,M.;Plastaras,J.P.;Marnett,L.J.Reactionofmalondialdehyde-DNA
adducts with hydrazinessdevelopment of a facile assay for quantifica-
tion of malondialdehyde equivalents in DNA. Chem. Res. Toxicol.
2002, 15, 312–318.
(14) Kappe, C. O.; Dallinger, D. The impact of microwave synthesis on
drug discovery. Nat. ReV. Drug DiscoVery 2006, 5, 51–63.
(15) Larhed, M.; Moberg, C.; Hallberg, A. Microwave-accelerated homo-
geneous catalysis in organic chemistry. Acc. Chem. Res. 2002, 35,
717–727.
(16) Larhed, M.; Wannberg, J.; Hallberg, A. Controlled microwave heating
as an enabling technology: expedient synthesis of protease inhibitors
in perspective. QSAR Comb. Sci. 2007, 26, 51–68.
(17) Ersmark, K.; Larhed, M.; Wannberg, J. Microwave-enhanced medicinal
chemistry: a high-speed opportunity for convenient preparation of
protease inhibitors. Curr. Opin. Drug DiscoVery DeV. 2004, 7, 417–
427.
1
gave 12v (52.9 mg, 70%). H NMR (CD3OD, 400 MHz) δ 0.75
(s, 9H), 1.56–1.70 (m, 1H), 1.70–1.86 (m, 2H), 2.03–2.16 (m, 1H),
2.74–2.94 (m, 4H), 3.01–3.14 (m, 2H), 3.46 (s, 3H), 3.70 (s, 1H),
3.88–4.00 (m, 2H), 4.16–4.22 (m, 1H), 5.09 (d, J ) 4.8 Hz, 1H),
7.10–7.30 (m, 9H), 7.50–7.70 (m, 6H), 8.50–8.60 (m, 2H); MS
(m/z 708, M + H+). Anal. (C41H49N5O6 ·H2O) C, H, N.
(18) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C.-P. Application of
palladacycles in Heck type reactions. J. Organomet. Chem. 1999, 576,
23–41.
(19) Miller, J. F.; Andrews, C. W.; Brieger, M.; Furfine, E. S.; Hale, M. R.;
Hanlon, M. H.; Hazen, R. J.; Kaldor, I.; McLean, E. W.; Reynolds,
D.; Sammond, D. M.; Spaltenstein, A.; Tung, R.; Turner, E. M.; Xu,
R. X.; Sherrill, R. G. Ultra-potent P1 modified arylsulfonamide HIV
protease inhibitors: the discovery of GW0385. Bioorg. Med. Chem.
Lett. 2006, 16, 1788–1794.
Acknowledgment. We thank the Swedish Research Council
(VR) and the Swedish Foundation for Strategic Research (SSF)
for financial support, Seved Löwgren for help with preparation
of the protease, and Dr. Yogesh Sabnis for help with the
manuscript.
(20) Medivir data.
(21) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare,
J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero,
J. C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.;
Axel, M. G.; Ostovic, D.; Anderson, P. S.; Huff, J. R. L-735,524: the
design of a potent and orally bioavailable HIV protease inhibitor.
J. Med. Chem. 1994, 37, 3443–3451.
Note Added after Print Publication. To correct a printing error
related to Scheme 3, this paper was reposted on March, 14, 2008.
(22) Robinson, B. S.; Riccardi, K. A.; Gong, Y.-F.; Guo, Q.; Stock, D. A.;
Blair, W. S.; Terry, B. J.; Deminie, C. A.; Djang, F.; Colonno, R. J.;
Lin, P.-F. BMS-232632, a highly potent human immunodeficiency
virus protease inhibitor that can be used in combination with other
available antiretroviral agents. Antimicrob. Agents Chemother. 2000,
44, 2093–2099.
(23) Randolph, J. T.; DeGoey, D. A. Peptidomimetic inhibitors of HIV
protease. Curr. Top. Med. Chem. 2004, 4, 1079–1095.
(24) Molla, A.; Vasavanonda, S.; Kumar, G.; Sham, H. L.; Johnson, M.;
Grabowski, B.; Denissen, J. F.; Kohlbrenner, W.; Plattner, J. J.;
Leonard, J. M.; Norbeck, D. W.; Kempf, D. J. Human serum attenuates
the activity of protease inhibitors toward wild-type and mutant human
immunodeficiency virus. Virology 1998, 250, 255–262.
(25) Williams, G. C.; Sinko, P. J. Oral absorption of the HIV protease
inhibitors: a current update. AdV. Drug DeliVery ReV. 1999, 39, 211–
238.
Supporting Information Available: Experimental details and
spectroscopic data for 2–15, elemental analysis data, X-ray structure
determination details, and procedures for enzyme assay. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) AIDS Epidemic Update: December 2006; Joint United Nations
Programme on HIV/AIDS (UNAIDS/WHO): Geneva, 2006.
(2) Brik, A.; Wong, C.-H. HIV-1 protease: mechanism and drug discovery.
Org. Biomol. Chem. 2003, 1, 5–14.
(3) Randolph, J. T.; DeGoey, D. A. Peptidomimetic inhibitors of HIV
protease. Curr. Top. Med. Chem. 2004, 4, 1079–1095.
(4) Abdel-Rahman, H. M.; Al-Karamany, G. S.; El-Koussi, N. A.; Youssef,
A. F.; Kiso, Y. HIV protease inhibitors: peptidomimetic drugs and
future perspectives. Curr. Med. Chem. 2002, 9, 1905–1922.
(5) Rodríguez-Barrios, F.; Gago, F. HIV protease inhibition: limited recent
progress and advances in understanding current pitfalls. Curr. Top.
Med. Chem. 2004, 4, 991–1007.
(26) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.; Lövgren, S.;
Classon, B.; Danielson, U. H.; Kvarnström, I.; Vrang, L.; Unge, T.;
Samuelsson, B.; Hallberg, A. Design and fast synthesis of C-terminal
duplicated potent C2-symmetric P1/P1′-modified HIV-1 protease
inhibitors. J. Med. Chem. 1999, 42, 3835–3844.
(6) Clavel, F.; Hance, A. J. HIV drug resistance. N. Engl. J. Med. 2004,
350, 1023–1035.
(7) de Mendoza, C.; Soriano, V. Resistance to HIV protease inhibitors:
mechanisms and clinical consequences. Curr. Drug Metab. 2004, 5,
321–328.
(8) Ekegren, J. K.; Unge, T.; Safa, M. Z.; Wallberg, H.; Samuelsson, B.;
Hallberg, A. A new class of HIV-1 protease inhibitors containing a
tertiary alcohol in the transition-state mimicking scaffold. J. Med.
Chem. 2005, 48, 8098–8102.
(9) Ekegren, J. K.; Ginman, N.; Johansson, Å.; Wallberg, H.; Larhed,
M.; Samuelsson, B.; Unge, T.; Hallberg, A. Microwave accelerated
synthesis of P1′-extended HIV-1 protease inhibitors encompassing a
(27) Rich, D. H. Pepstatin-derived inhibitors of aspartic proteinases. A close
look at an apparent transition-state analog inhibitor. J. Med. Chem.
1985, 28, 263–273.
(28) Rich, D. H.; Bernatowicz, M. S.; Agarwal, N. S.; Kawai, M.; Salituro,
F. G.; Schmidt, P. G. Inhibition of aspartic proteases by pepstatin and
3-methylstatine derivatives of pepstatin. Evidence for collected-
substrate enzyme inhibition. Biochemistry 1985, 24, 3165–3173.
(29) Agarwal, N. S.; Rich, D. H. Inhibition of cathepsin D by substrate
analogs containing statine and by analogs of pepstatin. J. Med. Chem.
1986, 29, 2519–2524.
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