ACS Medicinal Chemistry Letters
Page 6 of 7
(4) Midde, N. M.; Patters, B. J.; Rao, P.; Cory, T. J.; Kumar, S. Invesꢀ
tigational protease inhibitors as antiretroviral therapies. Expert Opin.
Investig. Drugs, 2016, 25 (10), 1189–1200.
1
2
3
4
5
6
7
8
Table 1. Enzyme affinity and antiviral activity of key mol-
ecules
(5) Bungard, C. J.; Williams, P. D.; Ballard, J. E.; Bennett, D. J.;
Beaulieu, C.; BahnckꢀTeets, C.; Carroll, S. S.; Chang, R. K.; Dubost,
D. C.; Fay, J. F.; Diamond, T. L.; Greshock, T. J.;Hao, L.; Holloway,
K. M.; Felock, P. J.; Gesell, J. J.; Su, H.; Manikowski, J. J.; McKay,
D. J.; Miller, M.; Min, X.; Molinaro, C.; Moradei, O. M.; Nantermet,
P. J.; Nadeau, C.; Sanchez, R. I.; Satyanarayana, T.; Shipe W. D.;
Sanjay, S. K.; Truong, V. L.; Vijayasaradhi, S.; Wiscount, C. M.;
Vacca, J. P.; Crane, S. N.; McCauley, J. A. Discovery of MKꢀ8718,
an HIVꢀ1 protease inhibitor containing a novel morpholine aspartate
binding group. ACS Med. Chem. Lett., 2016, 7 (7), 702–707.
(6) Jaskolski, M.; Tomasselli, A. G.; Sawyer, T. K.; Staples, D. G.;
Heinrikson, R. L.; Schneider, J.; Kent, S. B.; Wlodawer, A., Structure
at 2.5ꢀA resolution of chemically synthesized human immunodefiꢀ
ciency virus type 1 protease complexed with a hydroxyethyleneꢀbased
inhibitor, Biochemistry 1991, 30, (6), 1600ꢀ9.
(7) Dandache, S.; Coburn, C. A.; Oliveira, M.; Allison, T. J.; Holꢀ
loway, M. K.; Wu, J. J.; Stranix, B. R.; Panchal, C.; Wainberg, M. A.;
Vacca, J. P. J. PLꢀ100, a novel HIVꢀ1 protease inhibitor displaying a
high genetic barrier to resistance: an in vitro selection study. Med.
Virol. 2008, 12, 2053ꢀ63.
(8) Tiwari, P. K.; Aidhen, I. S. A Weinreb amide based building block
for convenient access to β,βꢀdiarylacroleins: Synthesis of 3ꢀ
arylindanones. Eur. J. Org. Chem. 2016, 15, 2637ꢀ2646.
Enzyme19
IC50 (pM)
Antiviral11
EC50 (nM)
Compound
700 ± 600
12 ± 1
27 ± 7
2.8 ± 0.4
12 ± 4
7 ± 2
MK-8718
38
9
40 ± 30
13 ± 3
Atazanavir
Darunavir
10
11
12
13
14
15
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18
19
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21
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25
26
27
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45
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60
ASSOCIATED CONTENT
Supporting Information
Synthetic experimental details for the synthesis of 7, 8, 18 – 21,
and 35, descriptions of primary biological assays, procedures for
coꢀcrystallization studies, and a table of crystallographic statisꢀ
tics, along with in vivo rat pharmacokinetic data for 7, 18, 20, and
21 are available free of charge (PDF) on the ACS Publications
website at DOI: xxxxxx. Xꢀray crystallographic data for 7, 18, 19,
20, 21, and 35 bound to HIVꢀ1 protease have been deposited in
the RCSB protein data bank (pdb codes 6B36, 6B3C, 6B3F,
6B38, 6B3G, 6B3H).
(9) Dess, D. B.; Martin, J. C. Readily accessible 12ꢀIꢀ5 oxidant for the
conversion of primary and secondary alcohols to aldehydes and
ketones. J. Org. Chem. 1983, 48, 4155ꢀ4156.
(10) Carmosin, R. J.; Carson, J. R.; Pitis, P. M. Preparation of octahyꢀ
dropyrroloꢀ[3,4ꢀc]carbazoles
WO9965911A1.
useful
as
analgesic
agents.
AUTHOR INFORMATION
Corresponding Author
(11) Assay for inhibition of viral infection as described in the supportꢀ
ing information, run in the presence of 50% NHS, potency reported as
a EC50 (average of at least n=2 runs).
(12) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Expedited
protocol for construction of chiral regioselectively Nꢀprotected monoꢀ
substituted piperazine, 1,4ꢀdiazepane building blocks. J. Org. Chem.,
2009, 74, (15), 5652–5655.
(13) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. Gold(I)ꢀ
catalyzed asymmetric aldol reaction of NꢀmethoxyꢀNꢀmethylꢀαꢀ
isocyanoacetamide (αꢀisocyano Weinreb amide). An efficient syntheꢀ
sis of optically active βꢀhydroxy αꢀamino aldehydes and ketones. J.
Org. Chem. 2016, 15, 2637ꢀ2646.
(14) Samanta, K.; Panda, G. Regioselective ringꢀopening of amino
acidꢀderived chiral aziridines: an easy access to cisꢀ2,5ꢀdisubstituted
chiral piperazines. Chem. Asian J. 2011, 6, 189 – 197.
(15) Nyasse, B.; Grehn, L.; Ragnarsson, U. Mild, efficient cleavage of
arenesulfonamides by magnesium reduction. Chem. Commun. 1997,
11, 1017ꢀ1018
(16) Zhan, Z. Preparation of ruthenium complex ligand, ruthenium
complexes, supported ruthenium complex catalysts for olefin metathꢀ
esis, WO 2007003135A1.
(17) Corey, E. J.; Fuchs, P. L. Synthetic method for conversion of
formyl groups into ethynyl groups. Tetrahedron Lett. 1972, 36, 3769ꢀ
72
(18) Sonogashira, K., Development of PdꢀCu catalyzed crossꢀ
coupling of terminal acetylenes with sp2ꢀcarbon halides. J. Organ-
omet. Chem. 2002, 653, (1ꢀ2), 46ꢀ49.
(19) Assay for inhibition HIVꢀ1 protease as described in the supportꢀ
ing information, potency reported as an IC50 (average of at least n=2
runs).
* Eꢀmail: christopher_bungard@merck.com
Phone: 215ꢀ652ꢀ5002
ABBREVIATIONS
HIV = human immunodeficiency virus; Ile = isoleucine; Asp =
aspartic acid; Boc = tertꢀbutyloxycarbonyl; 1,2ꢀDCE = 1,2ꢀ
dichloroethane; DIAD = diisopropyl azodicarboxylate; DME =
1,2ꢀdimethoxyethane; DMF = dimethylformamide; EtOAc = ethyl
acetate; MeOH = methanol; NEt3 = triethylamine; PBu3 = tribuꢀ
tylphosphine; RT
=
room temperature; T3P®
=
1ꢀ
propanephosphonic anhydride; THF = tetrahydrofuran; TFA =
trifluoroacetic acid.
REFERENCES
(1) EricksonꢀViitanen, S.; Manfredi, J.; Viitanen, P.; Tribe, D. E.;
Tritch, R.; Hutchison, C. A., 3rd; Loeb, D. D.; Swanstrom, R., Cleavꢀ
age of HIVꢀ1 gag polyprotein synthesized in vitro: sequential cleavꢀ
age by the viral protease. AIDS Res Hum Retroviruses 1989, 5, (6),
577ꢀ91.
(2) Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. J.; Heimbach,
J. C.; Dixon, R. A. F.; Scolnick, E. M.; Sigal, I. S., Active human
immunodeficiency virus protease is required for viral infectivity.
Proc. Natl. Acad. Sci. U. S. A. 1988, 85, (13), 4686ꢀ90.
(3) Ghosh, A. K.; Osswald, H. L.; Prato, G. Recent progress in the
development of HIVꢀ1 protease inhibitors for the treatment of
HIV/AIDS. J. Med. Chem., 2016, 59 (11), 5172–5208.
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