Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus

Article abstract of DOI:10.1016/j.bmcl.2013.05.021

The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1 μM, respectively.

Full text of DOI:10.1016/j.bmcl.2013.05.021

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3709–3712
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus,
norovirus, and coronavirus
Sivakoteswara Rao Mandadapu a, , Pathum M. Weerawarna a, , Allan M. Prior b, Roxanne Adeline Z. Uy a,
Sridhar Aravapalli a, Kevin R. Alliston a, Gerald H. Lushington c, Yunjeong Kim d, Duy H. Hua b,
Kyeong-Ok Chang d, William C. Groutas a,
⇑
a Department of Chemistry, Wichita State University, Wichita, KS 67260, USA
b Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
c LiS Consulting, Lawrence, KS 66046, USA
d Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases
of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective
concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and
Received 2 April 2013
Revised 29 April 2013
Accepted 7 May 2013
Available online 16 May 2013
coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1
respectively.
lM,
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrocyclic inhibitors
3C and 3CL proteases
Picornavirus-like supercluster pathogens
The picornavirus-like protease supercluster includes viruses in
the Picornaviridae, Coronaviridae, and Caliciviridae families. Many
human pathogens of major medical and economic importance be-
long to these virus families. For instance, the family Picornaviridae
includes enterovirus (enterovirus, EV; coxsackievirus, CV; poliovi-
rus, PV), human rhinovirus (HRV), and hepatitis A virus (HAV).1,2
Non-polio enteroviruses are responsible for 10–15 million symp-
tomatic infections in the US each year,3 while HRV is the major
causative agent of upper respiratory tract infections.4 In the Coro-
naviridae family, severe acute respiratory syndrome (SARS) caused
by SARS-coronavirus (SARS-CoA) is a recognized global threat to
public health.5 Noroviruses belong to the Norovirus genus of the
Caliciviridae family and are highly contagious human pathogens
that are the most common cause of food borne and water borne
acute viral gastroenteritis.6 Thus, norovirus infection constitutes
an important public health problem. There are currently no vac-
cines (except for poliovirus) or specific antiviral agents for combat-
ing infections caused by the aforementioned viruses; thus, there is
an urgent and unmet need for the discovery and development of
broad spectrum small-molecule therapeutics and prophylactics
for these important pathogens.7–10
The picornaviral genome consists of a positive sense, single-
stranded RNA of ꢀ7.5 kb in length that encodes a large precursor
polyprotein that requires proteolytic processing to generate ma-
ture viral proteins.1,2 Processing of the polyprotein is primarily
mediated by the viral 3C protease (3Cpro). Likewise, the ꢀ30 kb
genome of SARS-CoV comprises both nonstructural and structural
regions. Two polyproteins (designated as pp1a and pp1ab) encoded
by the viral genome undergo proteolytic processing by two prote-
ases: a chymotrypsin-like cysteine protease (3C-like protease,
3CLpro) and a papain-like protease (PLpro), to generate function-
ally active proteins. Finally, the 7–8 kb RNA genome of noroviruses
encodes a polyprotein that is processed by a 3C-like protease
(3CLpro) to generate mature proteins.11 Although there is high ge-
netic diversity among these viruses, 3Cpro and 3CLpro are highly
conserved, as well as essential for virus replication.
Inspection of the crystal structures of picornavirus 3Cpro12–15
and norovirus 3CLpro,16–19 reveals that the proteases share in com-
mon a chymotrypsin-like fold, a Cys-His-Glu/Asp catalytic triad
(EV and CV 3Cpro, and NV 3CLpro) or Cys-His dyad (SARS-CoV
3CLpro),20 an extended binding site, and a preference for cleaving
at Gln-Gly ðP1 ꢁ P0 Þ junctions in protein and synthetic peptidyl
1
substrates (vide infra). The confluence of structural similarities in
the active sites, mechanism of action, and substrate specificity
preferences of EV and CV 3Cpro,12,13 SARS-CoV 3CLpro,20,21 and
NV 3CLpro11,17,22 (Table 1) suggests that a drug-like entity can be
fashioned that displays inhibitory activity against all three
⇑
Corresponding author. Tel.: +1 (316) 978 7374; fax: +1 (316) 978 3431.
E-mail address: bill.groutas@wichita.edu (W.C. Groutas).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.021

3710
S. R. Mandadapu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3709–3712
Table 1
way of pre-organizing a peptidyl transition state mimic in a
b-strand conformation suitable for binding to the active site of a
protease;26–28 (c) in general, macrocyclization increases affinity
by reducing the loss of entropy upon inhibitor binding, as well as
cellular permeability, and proteolytic stability;29 (d) macrocycliza-
tion improves drug-like characteristics;30,31 (e) the plasticity of the
Substrate specificity of the 3C and 3C-like proteases of viruses in the picornavirus-like
protease supercluster
P10
P20
Viral 3Cpro or 3CLpro
P5
P4
P3
P2
P1
EV71
E
E
S
D/E
A
A
A
F/Y
V/L/T
L
V/T/K
H/Q/E
L/F
F
L
Q
Q
Q
Q
G
G
A/S
G
P
P
G
P
CVA16
SARS-CoV
NV
S3 subsite in the 3C and 3CL proteases was exploited in the design
L
of macrocyclic inhibitor (I) by tethering the P1 Gln side chain to the
P3 residue side chain; and, (e) computational and modeling studies
suggested that a ring size corresponding to n = 3 would produce
good receptor binding and minimal intra-ligand strain.
proteases, making them appealing targets for the discovery of
broad spectrum antiviral agents.16,23
Based on the aforementioned considerations, inhibitor (I) was
assembled in a convergent fashion by first constructing fragments
2 and 4, followed by subsequent coupling of the two fragments to
generate acyclic precursor 5 (Scheme 1). Cyclization was subse-
quently accomplished using click chemistry.32–35 Thus, fragment
2 was synthesized by coupling (L) Boc-protected propargyl glycine
with (L) leucine methyl ester using EDCI/HOBt/DIEA/DMF to yield
the dipeptidyl ester which was subsequently treated with dry
HCl in dioxane to remove the N-terminal Boc protecting group.
Reaction with benzylchloroformate yielded the Cbz-protected es-
ter which was hydrolyzed with LiOH in aqueous THF to yield the
corresponding acid 2. EDCI-mediated coupling of commercially
available (L) Boc-Glu-OCH3 with NH2(CH2)nN3 (n = 3), followed by
removal of the Boc group, yielded fragment 4.36 The amino alkyl
azide was conveniently synthesized by converting BocNH(CH2)nOH
to the mesylate via treatment with methanesulfonyl chloride in the
presence of triethylamine, followed by reaction with sodium azide
in DMF and removal of the protective group. Coupling of fragment
2 with 4 using standard coupling conditions yielded acyclic
precursor 5 which was treated with Cu(I)Br/DBU in dichlorometh-
ane to furnish compound 6 in 45% yield. Compound 6 was treated
with lithium borohydride to yield alcohol 7 (84% yield) which,
upon Dess–Martin periodinane oxidation,37 and subsequent purifi-
cation gave macrocyclic aldehyde 8 (Scheme 1, structure (I), n = 3,
Picornavirus 3Cpro,2 SARS-CoV 3CLpro23 and NV 3CLpro24 have
been the subject of intense investigations. We report herein the de-
sign, synthesis, and in vitro evaluation of a representative member
of a new class of macrocyclic transition state inhibitors (I) (Fig. 1)
that is effective against all three proteases. To our knowledge, this
is the first report describing the inhibition of 3Cpro and 3CLpro of
pathogens belonging to the picornavirus-like protease superclu-
ster, by a macrocyclic inhibitor.
The design of macrocyclic inhibitor (I) rested on the following
considerations: (a) proteases are known to recognize their ligands
in the b-strand conformation;25 (b) macrocyclization is an effective
O
R
H
N
CbzHN
X
N
H
N
O
N
N
NH
O
(CH2)n
(I)
Figure 1. General structure of macrocyclic inhibitor (I).
O
R
O
R
BocHN
COOH
a, b
H2N
(HCl)
CbzHN
N
H
COOCH3
N
H
COOH
c, d
O
R
2
1
H
N
f
CbzHN
COOCH3
g
N
H
H2N
COOCH3
BocHN
COOCH3
b
O
BocHN
COOCH3
e
(HCl)
(CH2)n
N3
N
O
H
(CH2)n
(CH2)n
COOH
N3
N3
N
O
N
O
H
5
H
4
3
O
R
O
R
O
R
H
H
N
H
N
CbzHN
N
COOCH3
O
X
CbzHN
CbzHN
N
H
N
N
H
N
N
OH
O
H
h
O
O
O
i
N
N
N
N
N
N
NH
O
NH
N
NH
(CH2)n
(CH2)n
(CH2)n
(I)
7
6
(8, R=isobutyl, n=3, X=CHO)
Scheme 1. Reagents and conditions: (a) EDCI/HOBt/DIEA/DMF then (L) NH2CHRCOOCH3; (b) HCl/dioxane; (c) benzylchloroformate/TEA/DCM; (d) LiOH/aq THF; (e) EDCI/
HOBt/DIEA/DMF then NH2(CH2)nN3; (f) EDCI/HOBt/DIEA/DMF; (g) Cu(I)Br/DBU/DCM; (h) LiBH4/THF; (i) Dess–Martin periodinane.

S. R. Mandadapu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3709–3712
3711
prepositioning of inhibitor 8 into each of the three protease recep-
tors, which was accomplished in PYMOL45 via manual docking. PYMOL
was then used to produce a computational framework for refining
the docked conformation as follows: a ligand–receptor complex
was generated by protonating the preliminary receptor–ligand
complex (according to physiological pH with anionic aspartate
and glutamate residues, and cationic lysine and arginine residues),
then retaining only the ligand plus all complete residues with at
least one atom located within no more than 6.0 Å from any ligand
atom. The resulting complex models were then permitted to un-
dergo 1000 molecular mechanics optimization steps in Avogadro46
using the MMFF94 force field and electrostatic charge model.47 The
resulting complexes were then rendered in PYMOL. The computa-
tional studies indicate that inhibitor 8 is capable of nestling snugly
in the active site of the 3C and 3CL proteases.
In summary, we report herein for the first time the inhibition
of the 3Cpro and 3CL pro of viral pathogens belonging to the
picornavirus-like protease supercluster by a macrocyclic inhibi-
tor. A full account describing the exploration of R, linker, n (ring
size), and the nature of warhead X, will be reported in due
course.
Acknowledgment
The generous financial support of this work by the National
Institutes of Health (AI081891) is gratefully acknowledged.
References and notes
1. Racaniello, V. R. In Picornaviridae: The Viruses and their Replication in Fields
Virology; Knipe, D. M., Howley, P. M., Eds.; Lippincott, Williams & Wilkins:
Philadelphia, 2007; Vol. 1, pp 795–838.
2. The Picornaviruses; Ehrenfeld, E., Domingo, E., Roos, R. P., Eds.; ASM Press:
Washington, DC, 2010.
3. (a) Solomon, T.; Lewtwaite, P.; Perera, D.; Cardosa, M. J.; McMinn, P.; Ooi, M. H.
Lancet Infect. Dis. 2010, 10, 778; (b) McMinn, P. C. Curr. Opin. Virol. 2012, 2, 199.
4. (a) Turner, R. B.; Couch, R. B. In Rhinoviruses in Fields Virology; Knipe, D. M.,
Howley, P. M., Eds.; Lippincott, Williams & Wilkins: Philadelphia, 2007; Vol. 1,
pp 895–909; (b) Winther, B. Proc. Am. Thorac. Soc. 2011, 8, 79; (c) Ren, L.; Xiang,
Z.; Wang, J. Curr. Infect. Dis. Rep. 2012, 14, 284.
5. (a) Perlman, S.; Netland, J. Nat. Rev. Microbiol. 2009, 7, 439; (b) Khan, G. Virol. J.
2013, 10, 66.
6. (a) Atmar, R. L. Food Environ. Virol. 2010, 2, 117; (b) Patel, M. M.; Hall, A. J.;
Vinje, J.; Parashar, U. D. J. Clin. Virol. 2009, 44, 1.
7. (a) Ramajayam, R.; Tan, K. P.; Liang, P. H. Biochem. Soc. Trans. 2011, 39, 1371; (b)
Tong, T. R. Infect. Disord. Drug Targets 2009, 9, 223.
Figure 2. Computationally predicted conformers for inhibitor
8 bound to (A)
8. Thibaut, H. J.; De Palma, A. M.; Neyts, J. Biochem. Pharmacol. 2012, 83, 185.
9. Steuber, H.; Hilgenfeld, R. Curr. Top. Med. Chem. 2010, 10, 323.
10. Eckardt, A. J.; Baumgart, D. C. Recent Pat. Antiinfect. Drug Disc. 2011, 6, 54.
11. Blakeney, S. J.; Cahill, A.; Reilly, P. A. Virology 2003, 308, 216.
12. (a) Cui, S.; Wang, J.; Fan, T.; Qin, B.; Guo, L.; Lei, X.; Wang, J.; Wang, M.; Jin, Q. J
.Mol. Biol. 2011, 408, 449; (b) Wang, J.; Fan, T.; Yao, X.; Guo, L.; Lei, X.; Wang, J.;
Jin, Q.; Cui, S. J. Virol. 2011, 85, 10021.
norovirus 3CLpro, (B) coxsackie virus 3Cpro, and (C) SARS-CoV 3CLpro. Inhibitor is
rendered as CPK-colored sticks with black carbon atoms. Protein receptors are
shown as Connolly surfaces colored as follows: yellow = nonpolar aryl, alkyl and
thioalkyl; white = weakly polar aryl and alkyl; cyan = polar H; blue = polar N;
red = polar O.
13. (a) Lu, G.; Qi, J.; Chen, Z.; Xu, X.; Gao, F.; Lin, D.; Qian, W.; Liu, H.; Jiang, H.; Yan,
J.; Gao, G. F. J. Virol. 2011, 85, 10319; (b) Kuo, C.-J.; Shie, J.-J.; Fang, J.-M.; Yen,
G.-R.; Hsu, J. T.-A.; Liu, H.-G.; Tseng, S.-N.; Chang, S.-C.; Lee, C.-Y.; Shi, S.-R.;
Liang, P.-H. Bioorg. Med. Chem. 2008, 16, 7388.
14. Allaire, M.; Chernaia, M. M.; Malcolm, B. A.; James, M. N. Nature 1994, 369, 72.
15. Seipelt, J.; Guarne, A.; Bergmann, E.; James, M.; Sommergruber, W.; Fita, I.;
Skern, T. Virus Res. 1999, 62, 159.
R = isobutyl, X = CHO), as a white solid.38 The inhibitory activity of
aldehyde 8 was evaluated in vitro as previously described.16,39–42
Compound 8 displayed inhibitory activity against NV 3CLpro
(IC50 5.1
lM), enterovirus (CVB3 Nancy strain) 3Cpro (1.8
lM),
16. Kim, Y.; Lovell, S.; Tiew, K. C.; Gunnam, G. R.; Alliston, K. R.; Battaille, K. P.;
Groutas, W. C.; Chang, K. O. J. Virol. 2012, 86, 11754.
and SARS-CoV 3CLpro (IC50 15.5
lM).
In order to gain insight and understanding into the binding of
inhibitor 8 to the active site of each protease, computer modeling
was used (Fig. 2). Thus, the receptor structures were prepared from
the following protein data bank (PDB) crystal structures: (A) NV
3CLpro from 2IPH,17 (B) CV 3C pro from 3ZZB,43 and (C) SARS-
CoV 3CLpro from 2ZU5.44 These three receptor models were chosen
by virtue of having cocrystallized ligands that each displayed the
following three features consistent with the likely binding mode
of inhibitor 8: (i) a covalent attachment to the catalytically active
cysteine (analogous to the terminal aldehyde in inhibitor 8), (ii)
branched alkyl, as per isobutyl group in 8, and (iii) aryl (phenylal-
anine or Cbz), as per Cbz in 8. This permitted the intelligent
17. Hussey, R. J.; Coates, L.; Gill, R. S.; Erskine, P. T.; Coker, S. F.; Mitchell, E.; Cooper,
J. B.; Wood, S.; Broadbridge, R.; Clarke, I. N.; Lambden, P. R.; Shoolingin-Jordan,
P. M. Biochemistry 2011, 50, 240.
18. Zeitler, C. E.; Estes, M. K.; Venkataraman, P. B. V. J. Virol. 2006, 80, 5050.
19. Nakamura, K.; Someya, Y.; Kumasaka, T.; Ueno, G.; Yamamoto, M.; Sata, T.;
Takeda, N.; Miyamura, T.; Tanaka, N. J. Virol. 2005, 79, 13685.
20. Akaji, K.; Konno, H.; Mitsui, H.; Teruya, K.; Shimamoto, Y.; Hattori, Y.; Ozaki, T.;
Kusunoki, M.; Sanjoh, A. J. Med. Chem. 2011, 54, 7962. and references cited
therein.
21. (a) Goetz, D. H.; Choe, Y.; Hansell, E.; Chen, Y. T.; McDowell, M.; Jonsson, C. B.;
Roush, W. R.; McKerrow, J.; Craik, C. S. Biochemistry 2007, 46, 8744; (b) Chuck,
C. P.; Chong, L. T.; Chen, C.; Chow, H. F.; Wan, D. C. C.; Wong, K. B. PLoS One
2010, 5, e13197; (c) Zhu, L.; George, S.; Schmidt, M. F.; Al-Gharabli, S. I.;
Rademann, J.; Hilgenfeld, R. Antiviral Res. 2011, 92, 204; (d) Chuck, C. P.; Chow,
H. F.; Wan, D. C.; Wong, K. B. PLoS One 2011, 6, e27228.

3712
S. R. Mandadapu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3709–3712
22. (a) Hardy, M. E.; Crone, T. J.; Brower, J. E.; Ettayebi, K. Virus Res. 2002, 89, 29; (b)
Someya, Y.; Takeda, N.; Miyamura, T. Antiviral Res. 2005, 110, 91.
Chem. 2002, 9, 963; (g) Edwards, M. P.; Price, D. A. Annu. Rep. Med. Chem. 2010,
45, 381.
23. Barnard, D. L.; Kumaki, Y. Future Virol. 2011, 6, 615.
32. Roper, S.; Kolb, H. C. Methods Princ. Med. Chem. 2006, 34, 313.
33. Kelly, A. R.; Wei, J.; Kesavan, S.; Marie, J. C.; Windmon, N.; Young, D. W.;
Marcaurelle, L. A. Org. Lett. 2009, 11, 2257.
24. (a) Tiew, K.-C.; He, G.; Aravapalli, S.; Mandadapu, S. R.; Gunnam, M. R.; Alliston,
K. R.; Lushington, G. H.; Kim, Y.; Chang, K.-O.; Groutas, W. C. Bioorg. Med. Chem.
Lett. 2011, 21, 5315; (b) Dou, D.; Tiew, K.-C.; He, G.; Mandadapu, S. R.;
Aravapalli, S.; Alliston, K. R.; Kim, Y.; Chang, K.-O.; Groutas, W. C. Bioorg. Med.
Chem. 2011, 19, 5975; (c) Dou, D.; Mandadapu, S. R.; Alliston, K. R.; Kim, Y.;
Chang, K.-O.; Groutas, W. C. Bioorg. Med. Chem. 2011, 19, 5749; (d) Dou, D.;
Mandadapu, S. R.; Alliston, K. R.; Kim, Y.; Chang, K.-O.; Groutas, W. C. Eur. J.
Med. Chem. 2012, 47, 59; (e) Dou, D.; He, G.; Mandadapu, S. R.; Aravapalli, S.;
Kim, Y.; Chang, K.-O.; Groutas, W. C. Bioorg. Med. Chem. Lett. 2012, 22, 377; (f)
Dou, D.; Tiew, K.-C.; Mandadapu, S. R.; Gunnam, M. R.; Alliston, K. R.; Kim, Y.;
Chang, K.-O.; Groutas, W. C. Bioorg. Med. Chem. 2012, 20, 2111; (g) Mandadapu,
S. R.; Gunnam, M. R.; Tiew, K. C.; Uy, R. A. Z.; Prior, A. M.; Alliston, K. R.; Hua, D.
H.; Kim, Y.; Chang, K. O.; Groutas, W. C. Bioorg. Med. Chem. Lett. 2013, 23, 62; (h)
Mandadapu, S. R.; Weerawarna, P. M.; Gunnam, M. R.; Alliston, K. R.;
Lushington, G. H.; Kim, Y.; Chang, K. O.; Groutas, W. C. Bioorg. Med. Chem.
Lett. 2012, 22, 4820; (i) Pokheil, L.; Kim, Y.; Thi, D.; Nguyen, T.; Prior, A. M.; Lu,
J.; Chang, K. O.; Hua, D. H. Bioorg. Med. Chem. Lett. 2012, 22, 3480.
34. Pehere, A. D.; Abell, A. D. Org. Lett. 2012, 14, 1330.
35. Zhang, J.; Kemmink, J.; Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2011, 13,
3438.
36. All compounds were characterized by 1H NMR and HRMS, and had a >95%
purity.
37. Bogen, S. L.; Arasappan, A.; Velazquez, F.; Blackman, M.; Huelgas, R.; Pan, W.;
Siegel, E.; Nair, L. G.; Venkatraman, S.; Guo, Z.; Dolle, R.; Shi, N. Y.; Njoroge, F.
Bioorg. Med. Chem. 1854, 2010, 18.
38. Compound 8: 1H NMR (DMSO-d6): d 9.49 (s, 1H), 7.83 (s, 1H), 7.30 (m, 5H), 5.10
(m, 2H), 4.50 (m, 1H), 4.40 (m, 2H), 3.80 (m, 2H), 3.11 (m, 2H), 2.88 (m, 2H),
2.98–2.24 (m, 5H), 1.49–1.80 (m, 5H), 0.81–0.99 (m, 6H). HRMS. Calculated
M+Na 578.2703. Found mass: 578.2702.
39. Chang, K. O.; Sosnovtsev, S. V.; Belliot, G.; King, A. D.; Green, K. Y. Virology 2006,
2, 463.
40. Chang, K. O.; George, D. W. J. Virol. 2007, 22, 12111.
41. Chang, K. O. J. Virol. 2009, 83, 8587.
42. Kim, Y.; Thapa, M.; Hua, D. H.; Chang, K.-O. Antiviral Res. 2011, 89, 165.
43. Tan, J.; George, S.; Kusov, Y.; Perbandt, M.; Anemuller, S.; Mesters, J. R.; Norder,
H.; Coutard, B.; Lacroix, C.; Leyssen, P.; Neyts, J.; Hilgenfeld, R. J. Virol. 2013, 87,
4339. Protein data bank entry 3ZZB.
44. Lee, C. C.; Kuo, C. J.; Ko, T. P.; Hsu, M. F.; Tsui, Y. C.; Chang, S. C.; Yang, S.; Chen,
S. J.; Chen, H. C.; Hsu, M. C.; Shih, S. R.; Liang, P. H.; Wang, A. H.-J. J. Biol. Chem.
2009, 284, 7646.
25. (a) Tyndall, J. D.; Nall, T.; Fairlie, D. P. Chem. Rev. 2005, 105, 973; (b) Madala, P.
K.; Tyndall, J. D.; Nall, T.; Fairlie, D. P. Chem. Rev. 2010, 110, 3299.
26. Tyndall, J. D.; Fairlie, D. P. Curr. Med. Chem. 2001, 8, 893.
27. Gilon, C.; Halle, D.; Chorev, M.; Selinger, Z.; Byk, G. Biopolymers 1991, 31, 745.
28. Glenn, M. P.; Pattenden, L. K.; Reid, R. C.; Tyssen, D. P.; Tyndall, J. D.; Birch, C. J.;
Fairlie, D. P. J. Med. Chem. 2002, 45, 371.
29. Marsault, E.; Peterson, M. L. J. Med. Chem. 1961, 2011, 54.
30. McCreary, R. P.; Fairlie, D. P. Curr. Opin. Drug Disc. Dev. 1998, 1, 208.
31. (a) Meanwell, N. Chem. Res. Toxicol. 2011, 24, 1420; (b) Lipinski, C. A. J.
Pharmacol. Toxicol. Methods 2000, 44, 235; (c) Veber, D. F. J. Med. Chem. 2002,
45, 2615; (d) Ritchie, T. J.; Ertl, P.; Lewis, R. Drug Discovery Today 2011, 16, 65;
(e) Gleeson, M. P. J. Med. Chem. 2008, 51, 817; (f) Adessi, C.; Soto, C. Curr. Med.
45. The PYMOL Molecular Graphics System, Version 1.5, Schrödinger, LLC; 2012.
46. Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.;
Hutchison, G. R. J. Cheminf. 2012, 4, 17.
47. Halgren, T. A. J. Comput. Chem. 1998, 5–6, 490.