A structural screening approach to ketoamide-based inhibitors of cathepsin K

Article abstract of DOI:10.1016/j.bmcl.2005.03.023

Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P² elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.

Full text of DOI:10.1016/j.bmcl.2005.03.023

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2209–2213
A structural screening approach to ketoamide-based inhibitors
of cathepsin K
David G. Barrett,a,ꢀ John G. Catalano,a David N. Deaton,a,* Stacey T. Long,b
Robert B. McFadyen,a Aaron B. Miller,c Larry R. Miller,d
Kevin J. Wells-Knechte and Lois L. Wrightf
aDepartment of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
bDepartment of World Wide Physical Properties, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
cDiscovery Research Computational, Analytical, and Structural Sciences, GlaxoSmithKline, Research Triangle Park,
North Carolina 27709, USA
dDepartment of Molecular Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
eDepartment of Research Bioanalysis and Drug Metabolism, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
fDiscovery Research Biology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
Received 21 February 2005; revised 4 March 2005; accepted 7 March 2005
Available online 9 March 2005
Abstract—Several novel ketoamide-based inhibitors of cathepsin Khave been identified. Starting from a modestly potent inhibitor,
structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in
an orally bioavailable cathepsin Kinhibitor.
Ó 2005 Elsevier Ltd. All rights reserved.
Osteoporosis results from an imbalance in the normally
tightly coupled processes of bone formation and bone
resorption that maintain skeletal integrity.1 The
decreased bone mass resulting from this disequilibrium
increases fracture susceptibility. Bone is resorbed by
osteoclasts, which secrete protons and proteases that de-
grade the mineral and protein components of bone. The
C1A family cysteine protease cathepsin Kis highly ex-
pressed in osteoclasts and can rapidly hydrolyze the ma-
jor component of bone matrix, type I collagen, in
complex with glycosaminoglycans.2,3 Secretion of
cathepsin Kby the osteoclasts begins the degradation
of organic bone matrix. These initial resorption compo-
nents are endocytosed with cathepsin Kinto the osteo-
clasts, where further degradation occurs during
transcytosis. The resulting bone degradation products
are then secreted into the circulation.4 The importance
of cathepsin Kin the bone remodeling process has been
demonstrated in both animals and humans.
Pycnodysostosis, a rare human autosomal recessive trait
characterized by short stature, abnormal bone and tooth
development, increased bone mineral density, and in-
creased bone fragility, results from mutations in cathep-
5
sin Kthat impair its function.
The phenotype of
cathepsin K( À/À) mice is also osteopetrotic.6 Further-
more, small molecule inhibitors of cathepsin Khave
proven efficacious in attenuating bone resorption in ani-
mal models of osteoporosis.7
As part of a larger program to develop novel cathepsin
Kinhibitors for the treatment of osteoporosis, research-
ers from these laboratories recently reported the discov-
ery of the ketoamide cathepsin Kinhibitor 1 (IC50
=
1200 nM).8 In addition to a traditional medicinal
chemistry approach aimed at replacing the tert-butyl
group in order to optimize the P2–P3 carbamateꢁs inter-
action with S2–S3 subsites, a structural screening exer-
cise was also employed.9 Since the S2 subsite is the
deepest, most pronounced hydrophobic binding pocket
of the cathepsin Kactive site, this was perceived to be
a fruitful area for structure-based modeling. Furthermore,
Keywords: Ketoamide; Cathepsin K; Cysteine protease inhibitor;
Structural screening.
*
Corresponding author. Tel.: +1 919 483 6270; fax: +1 919 315
0430; e-mail: david.n.deaton@gsk.com
ꢀ Present address: Lilly Forschung GmbH, Essener Str. 93, 22419
Hamburg, Germany.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.023

2210
D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2209–2213
2
the cathepsin KS subsite contains key structural vari-
ances versus other human cysteine cathepsin endopro-
teases, offering opportunities for selectivity versus
cathepsins L & S.10
O
H
N
H
N
O
O
nBu
O
Ph
1
Structural screening, a reliable, cost effective, and time-
saving technique for lead generation/optimization, was
employed to diversify the P2 substituent for the genera-
tion of potential new lead compounds. The Available
Chemical Directory (ACD) was selected as the database
for screening. The ACD was searched for secondary
alcohols that could easily be incorporated into the P2
carbamate scaffold. This large set of commercially avail-
able chiral and achiral alcohols (ꢀ12,000) was then fil-
tered by size (<200 g/mol MW, ꢀ1600) and cost
(<$10/g) parameters. After filtering, the resulting set of
Figure 1. S2 subsite of the X-ray crystal structure of cathepsin Kwith
the P2 portions of inhibitors 6a–h docked into the enzyme. The
cathepsin Kcarbons are colored magenta with inhibitors 6a–h carbons
colored green. The semi-transparent white surface represents the
molecular surface, while hydrogen bonds are depicted as yellow dashed
lines. This figure was generated using PYMOL version 0.97 (Delano
Scientific, www.pymol.org).
alcohols was visually inspected using known cathepsin
11,12
Kcrystal structures as a guide.
Approximately 25
carbamates were synthesized virtually from these
remaining alcohols and docked into a model of the
cathepsin Kactive site derived from an X-ray crystal
structure (Brookhaven Protein Data Bank, accession
number 1MEM).11 The virtual analogs were attached
to the protein via a covalent linkage between the active
site thiol 25Cys of cathepsin Kand the a-ketone to pro-
duce a hemithioketal. Both stereofacial modes of thiol
addition to the ketone were examined. The ꢂgrowꢁ algo-
rithm within the MVP program was used to dock the
virtual compounds.13 This algorithm ꢂgrowsꢁ the virtual
molecule one bond at a time and performs a systematic
search with each new bond. A minimization was done
for each member of the resulting ensemble of docked
structures to relax the strain and optimize non-bonded
interactions. Then, a scoring function was applied. The
active site of cathepsin Kwas held fixed during the
docking process. The covalent nature of these inhibitors
makes it difficult to calculate a score. The minimized
docked structure energy was compared to its ꢂunboundꢁ
counterpart that only contained 25Cys to represent
the hemithioketal. The modeled P2 portions of eight
analogs with calculated binding energies comparable
to those of inhibitor 1 are shown in Figure 1. The mod-
eled P2 moieties that filled more of the S2 subsite than
the starting tert-butyl group were selected for synthesis.
O
O
C
N
O
H
a, b
O
N
c
+
OH
R1
OH
R1
O
O
nBu
nBu
2a-2e
3
4a-4e
O
O
H
H
H
O
N
CN
nBu PPh3
5a-5e
O
N
N
Ph
d
R1
R1
O
O
nBu
O
6a-6e
Scheme 1. Reagents and conditions: (a) R1OH, PhMe, 85 °C, sealed
tube, 82–99%; (b) LiOHÆH2O, THF, H2O; 1 N HCl; (c) Ph3P=CCN,
DMAP, EDC, CH2Cl2, 35–70% over two reactions; (d) O3, CH2Cl2,
À78 °C; N2; (R)-a-methylbenzylamine, À78 °C to rt; AgNO3, THF,
H2O, 9–32%.
placement of cyanide by (R)-a-methylbenzylamine pro-
vided the desired ketoamides 6a–e.
The other procedure used to synthesize a-ketoamides in-
volved coupling the chloroformates formed from reac-
tion of the commercially available alcohols 2f–h with
phosgene to the known b-amino-a-hydroxy-amide 7.8
The resulting carbamates were subsequently oxidized
to the desired ketoamides as depicted in Scheme 2.
Two general routes were utilized to produce the a-keto-
amides. One protocol utilized the Wasserman acyl cyano-
phosphorane oxidative cleavage and amine coupling
procedure to synthesize the ketoamide moiety.14 As dis-
played in Scheme 1, commercially available alcohols 2a–e
were coupled to the known isocyanate 3.8 The resulting
carbamates were hydrolyzed to yield acids 4a–e.
Coupling of these acids with cyanomethyltriphenylphos-
phonium ylide gave the phosphoranes 5a–e. Then, oxi-
dative cleavage of the phosphorus–carbon double
bond with ozone generated an acyl nitrile. In situ dis-
OH
R1
O
O
H
H
H
H2N
N
N
N
a, b
OH
R1
+
nBu
O
Ph
O
nBu
O
Ph
2f-2h
7
6f-6h
Scheme 2. Reagents and conditions: (a) R1OH, 1.93 M COCl2 in
PhMe, pyridine, CH2Cl2, À20 °C to rt; 7, iPr2NEt, dioxane, 22–91%;
(b) Dess–Martin periodinane, CH2Cl2, 55–78% or TEMPO, 5%
NaOCl, KBr, NaHCO3, CH2Cl2, 42–89%.

D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2209–2213
2211
2
Table 1. Inhibition of human cathepsin Kby P analogs
Gratifyingly, all of the virtual screening derived analogs
were more potent than the tert-butyl carbamate 1. The
3,5-dimethyl cyclohexanol derived analogs 6a
(IC50 = 350 nM) and 6b (IC50 = 190 nM) exhibited slight
improvements in activity.15 The indanol analog 6c was
10-fold more potent than analog 1 (IC50 = 100 nM),
and the tetrahydronaphthol 6d (IC50 = 32 nM) was even
O
H
H
R1
N
N
O
nBu
O
Ph
a
IC50 (nM)
#
R1
Calculated binding energy
O
1
1200
À188.5
more active. The norborneol derivative 6e (IC50
=
26 nM) was equipotent to 6d, and the even bulkier
fenchyl alcohol derivative 6f (IC50 = 5.7 nM) was 4-fold
more active than 6e. The adamantanol analog 6g
O
O
6a
6b
6c
6d
6e
6f
350
190
100
32
À193.7
À189.7
À193.2
À194.2
À190.5
À175.4
À176.2
À194.5
(IC50 = 7.2 nM) and the pantolactone analog 6h (IC50
=
3.0 nM) were equipotent to 6f. The pantolactone deriva-
tive 6h was quite potent despite its reduced size relative
to 6f and 6g. Furthermore, it was surmised that its in-
creased hydrophilicity relative to the other analogs
might result in enhanced aqueous solubility and possibly
greater oral exposure. The increased potency presum-
ably arises from the presence of an additional hydrogen
bond between the lactone carbonyl and the backbone
NH of 66Gly in cathepsin Kas suggested by the docking
calculations.
O
O
Among the analogs selected for synthesis, no correlation
was found between calculated binding energies and mea-
sured inhibition constants. This lack of correlation may
be in part due to the static nature of the protein active
site model, which hampered scoring accuracy by not
allowing the protein to expand to accommodate larger
substituents such as those found in 6f and 6g, resulting
in lower scores for these inhibitors. Allowing the enzyme
to ꢂbreatheꢁ, might improve scoring and selection, but
would also increase calculation time. Despite these lim-
itations, this structural screening exercise enabled the
efficient identification of very potent cathepsin Kinhibi-
tors (Table 1).
26
O
O
O
5.7
7.2
3.0
6g
6h
O
O
O
a Inhibition of recombinant human cathepsin Kactivity in a fluores-
cence assay using 10 lM Cbz-Phe-Arg-AMC as substrate in 100 mM
NaOAc, 10 mM DTT, 120 mM NaCl, pH = 5.5. The IC50 values are
the mean of two or three inhibition assays, individual data points in
each experiment were within a 3-fold range of each other.
As shown in Table 2, these analogs were quite selective
versus the exopeptidases cathepsin B and cathepsin H.
They were less selective versus the more closely related
endopeptidase cathepsin L with selectivity ranging from
5 to 360-fold compared to cathepsin K. Selectivity
against cathepsins S and V, other closely related endo-
peptidases, was poor. In fact, analogs 6a and 6e were
actually more potent cathepsin S inhibitors than cathep-
sin Kinhibitors.
6i was synthesized as shown in Scheme 3. Protection of
the alcohol of known lactam 817 as the silyl ether, fol-
lowed by masking of the lactam nitrogen with benzyl-
chloroformate afforded the carbamate 9. The silyl
ether was then cleaved and the resulting alcohol 10 con-
verted into its corresponding chloroformate with phos-
gene. Coupling to amine 7 and cleavage of the benzyl
carbamate yielded 11. Finally, oxidation of the second-
ary alcohol 11 provided the ketoamide 6i.
Of the three most active derivatives, analog 6h was se-
lected for further profiling, because its calculated octa-
nol/water partition coefficient (6h (cLogP = 5.5) versus
6f (cLogP = 7.9) and 6g (cLogP = 7.3)) was substan-
tially lower than the other ketoamides. As shown in Ta-
ble 3, 6h was reasonably soluble in fasted state-simulated
intestinal fluid at pH = 6.8 (sol. = 0.24 mg/mL).16 How-
ever, 6h was cleared extremely rapidly from rat plasma
after i.v. dosing in male Han Wistar rats (Cl = 460 mL/
The lactam 6i (IC50 = 2.5 nM) was equipotent to the lac-
tone 6h (IC50 = 3.0 nM) and exhibited a similar selecti-
vity profile as well (Table 2). Lactam 6i was stable in
human plasma (t1/2 > 12 h) and more soluble in FS-
SIF than lactone 6h (sol. 6i FS-SIF = 0.80 mg/mL vs
6h FS-SIF = 0.24 mg/mL). The rat pharmacokinetic
profile also improved. Although still high, the clearance
(Cl = 48 mL/min/kg) was one-tenth that of lactone 6h,
and the terminal half-life (t1/2 = 62 min) increased
min/kg), resulting in a very short terminal half-life (t1/2
=
11 min). No systemic exposure was seen following p.o.
dosing. Plasma stability studies revealed that the lactone
of 6h was rapidly hydrolyzed to the hydroxyacid.
Surmising that in vivo generation of this hydroxyacid
might be the cause of the fast clearance of 6h, the lactam

2212
D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2209–2213
Table 2. Cathepsin B, H, L, S, and V inhibition and selectivity
#
Cat KCat B
IC50 (nM)
Cat H
IC50 (nM)a
Cat L
IC50 (nM)b
Cat S
IC50 (nM)c
Cat V
IC50 (nM)d
IC50 (nM)e
6a
6b
6c
6d
6e
6f
350
190
100
32
>13,000
>13,000
>13,000
>2000
>13,000
12,000
>5000
>500
>13,000
>13,000
>13,000
>2000
4400
6800
460
63
290
280
79
2800
2000
290
340
190
180
390
79
660
26
>13,000
>13,000
>5000
1000
1700
2600
410
19
30
5.7
7.2
3.0
2.5
6g
6h
6i
16
13
>500
>13,000
1400
150
18
29
a Inhibition of recombinant human cathepsin B activity in a fluorescence assay using 10 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, 120 mM NaCl, pH = 5.5. The IC50 values are the mean of two or three inhibition assays, individual data points in each experiment
were within a 2-fold range of each other.
b Inhibition of recombinant human cathepsin H activity in a fluorescence assay using 50 lM L-Arg-b-naphthalamide as substrate in 100 mM NaOAc,
10 mM DTT, 120 mM NaCl, pH = 5.5.
c Inhibition of recombinant human cathepsin L activity in a fluorescence assay using 5 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, 120 mM NaCl, pH = 5.5.
d Inhibition of recombinant human cathepsin S activity in a fluorescence assay using 10 lM Cbz-Val-Val-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, 120 mM NaCl, pH = 5.5.
e Inhibition of recombinant human cathepsin V activity in a fluorescence assay using 2 lM Cbz-Phe-Arg-AMC as substrate in 100 mM NaOAc,
10 mM DTT, 120 mM NaCl, pH = 5.5.
Table 3. Pharmacokinetics of P2 analogs
b
d
VSS (mL/kg)
#
cLogP
Sol. FS-SIFa (mg/mL)
t1=2 (min)
Clc (mL/min/kg)
Fe (%)
6h
6i
5.5
4.6
0.24
0.80
11
62
460
48
3400
1300
0
25
a FS-SIF is the equilibrium solubility in fasted state-simulated intestinal fluid at pH = 6.8. The values are the mean of two measurements.
b t1/2 is the i.v. terminal half-life dosed as a solution in 15% solutol/citrate buffer at pH 3.5 (2.5 mg/kg) to male Han Wistar rats. All in vivo
pharmacokinetic values are the mean of two experiments.
c Cl is the total clearance.
d VSS is the steady state volume of distribution.
e F is the oral bioavailability following a 5.0 mg/kg dose in 15% solutol/citrate buffer at pH 3.5.
of the inhibitor and the active site 25Cys of the enzyme
form a covalent hemithioketal intermediate, consistent
with the reversible nature of these time dependent, tight
binding inhibitors. As shown in ketoamide co-crystal
structures from this group,18 the hemithioketal hydroxyl
does not occupy the oxy-anion hole, but rather is stabi-
lized by hydrogen bonds to the catalytic histidine
O
O
O
Ph
OH
OTBS
HN
N
c
a, b
O
8
9
O
OH
O
O
H
N
H
Ph
O
O
N
Ph
OH
N
d, e
HN
O
(
162His) and the backbone carbonyl of 161Asn. Instead,
nBu
O
10
11
the carbonyl of the amide points into the oxyanion hole
where it is stabilized by hydrogen bonds to the side
chain NH of 19Gln and the backbone NH of 25Cys. This
differs from the other published aldehyde12,19 and ke-
tone20 cathepsin Kstructures, in which the active site
thiol attacks the carbonyl from the opposite face. Two
additional hydrogen bonds from the peptide backbone
recognition site of the enzyme and the carbamate further
stabilize the inhibitor. Thus, the carbamate carbonyl ac-
cepts a hydrogen bond from the backbone NH of 66Gly,
while the carbamate NH donates a hydrogen bond to
161Asn. Another additional hydrogen bond from the
carbonyl of the lactam to the backbone NH of 66Gly
is also present in the model, which may explain the sig-
nificant potency of this P2 group.
O
O
H
N
H
O
N
Ph
f
HN
O
nBu
O
6i
Scheme 3. Reagents and conditions: (a) TBSOTf, DMAP, Et3N,
CH2Cl2, 48%; (b) NaH, THF, 0 °C; PhCH2COCl, 0 °C to rt, 94%; (c)
TBAF, THF, 94%; (d) R1OH, 1.93 M COCl2 in PhMe, pyridine,
CH2Cl2, À20 °C to rt; 7, iPr2NEt, dioxane, 22–91%; (e) H2/Pd–C,
THF, 66%; (f) (COCl)2, DMSO, CH2Cl2, À60 °C; 11; Et3N, À60 °C to
rt; 56%.
six-fold. More importantly, the lactam 6i was orally bio-
available (F = 25%).
A model of inhibitor 6i docked into the active site of
cathepsin Kis shown in Figure 2. The a-keto moiety
Besides these hydrogen bond stabilizing interactions
with the protein, the S1 wall formed from 23Gly, 24Ser,

D. G. Barrett et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2209–2213
2213
3. Deaton, D. N.; Kumar, S. Prog. Med. Chem. 2004, 42,
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4. Vaaraniemi, J.; Halleen, J. M.; Kaarlonen, K.; Ylipah-
kala, H.; Alatalo, S. L.; Andersson, G.; Kaija, H.; Vihko,
P.; Vaananen, H. K. J. Bone Miner. Res. 2004, 19,
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5. Gelb, B. D.; Shi, G.-P.; Chapman, H. A.; Desnick, R. J.
Science 1996, 273, 1236.
6. Kiviranta, R.; Morko, J.; Alatalo, S. L.; NicAmhlaoibh,
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36, 159.
7. Stroup, G. B.; Lark, M. W.; Veber, D. F.; Bhattacharyya,
A.; Blake, S.; Dare, L. C.; Erhard, K. F.; Hoffman, S. J.;
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Nat. Struct. Biol. 1997, 4, 105.
Figure 2. Active site of the model structure of compound 6i complexed
with cathepsin K. The cathepsin K carbons are colored magenta with
inhibitor 6i carbons colored green. The semi-transparent white surface
represents the molecular surface, while hydrogen bonds are depicted as
yellow dashed lines. This figure was generated using PYMOL version
0.97 (Delano Scientific, www.pymol.org).
12. Catalano, J. G.; Deaton, D. N.; Furfine, E. S.; Hassell, A.
M.; McFadyen, R. B.; Miller, A. B.; Miller, L. R.;
Shewchuk, L. M.; Willard, D. H., Jr.; Wright, L. L.
Bioorg. Med. Chem. Lett. 2004, 14, 275.
13. Lambert, M. H. In Practical Application of Computer-
Aided Drug Design; Charifson, P. S., Ed.; Marcel Dekker:
New York, 1997; p 243.
64Gly, and 65Gly abuts the norleucine-derived P1 group
of the inhibitor, with one face of the n-butyl group form-
ing van der Waals interactions with the protease while
its terminal carbon is solvent exposed. Moreover, the
P2 lactam forms significant lipophilic interactions with
the S2 pocket composed of 67Tyr, 68Met, 134Ala,
163Ala, and 209Leu. These inhibitors do not contain a
P3 element that could potentially interact with the S3
subsite of cathepsin K. Incorporation of P3 groups
should enhance inhibitory activity at the cost of in-
creased size of the inhibitor.
14. Wasserman, H. H.; Petersen, A. K. Tetrahedron Lett.
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15. Many of the P2 moieties in these analogs contain a
stereogenic center adjacent to the carbamate. The epimers
of these analogs were poor virtual inhibitors of cathepsin
Kwhen modeled into the cathepsin Kactive site.
16. Dressman, J. B.; Amidon, G. L.; Reppas, C.; Shah, V. P.
Pharm. Res. 1998, 15, 11.
In summary, this report showcases a structural screening
approach for lead generation. Starting from the keto-
amide cathepsin Kinhibitor 1, the P2 substituent was re-
placed with commercially available groups identified
through molecular modeling. This exercise produced
significant gains in inhibitory activity, including analogs
6f, 6g, and 6h, which were over 100-fold more potent
than the starting ketoamide. Modification of inhibitor
6h produced analog 6i, which was equipotent and 25%
orally bioavailable. Subsequent reports will detail efforts
to improve the properties of this series of pantolactone-
derived ketoamide-based cathepsin Kinhibitors.
17. Kopelevich, V. M.; Bulanova, L. N.; Gunar, V. I.
Tetrahedron Lett. 1979, 3893.
18. Tavares, F. X.; Boncek, V.; Deaton, D. N.; Hassell, A. M.;
Long, S. T.; Miller, A. B.; Payne, A. A.; Miller, L. R.;
Shewchuk, L. M.; Wells-Knecht, K.; Willard, D. H., Jr.;
Wright, L. L.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 588.
19. Boros, E. E.; Deaton, D. N.; Hassell, A. M.; McFadyen,
R. B.; Miller, A. B.; Miller, L. R.; Paulick, M. G.;
Shewchuk, L. M.; Thompson, J. B.; Willard, D. H., Jr.;
Wright, L. L. Bioorg. Med. Chem. Lett. 2004, 14, 3425.
20. Marquis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.;
Yamashita, D. S.; Oh, H.-J.; Erhard, K. F.; Davis, L. D.;
Tomvaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.;
Ward, K.; Smith, B.; Levy, M.; Cummings, M. D.;
Haltiwanger, R. C.; Trescher, G.; Wang, B.; Hemling,
M. E.; Quinn, C. J.; Cheng, H. Y.; Lin, F.; Smith, W. W.;
Janson, C. A.; Zhao, B.; McQueney, M. S.; DꢁAlessio, K.;
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