Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R)

Article abstract of DOI:10.1016/j.bmcl.2004.05.003

A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.

Full text of DOI:10.1016/j.bmcl.2004.05.003

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3721–3725
Synthesis and biological evaluation of imidazole-based small
molecule antagonists of the melanocortin 4 receptor (MC4-R)
Thomas H. Marsilje,a,* Jonathan B. Roses,a Emily F. Calderwood,a Stephen G. Stroud,a
Nancy E. Forsyth,a Christopher Blackburn,a David L. Yowe,b Wenyan Miao,b
Stacey V. Drabic,b Marie D. Bohane,b J. Scott Daniels,c Ping Li,c Lijun Wu,b
Michael A. Patanea and Christopher F. Claibornea
aDepartment of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA
bDepartment of Metabolic Disease Biology, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA
cDepartment of Biotransformation, Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA
Received 22 March 2004; revised 3 May 2004; accepted 4 May 2004
Available online 28 May 2004
Abstract—A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported.
Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency
<100 nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of invol-
untary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The melanocortin receptors are a family of five G-pro-
tein coupled receptors, which have been shown to play
physiological roles in sexual behavior, pigmentation,
and body weight regulation.1 Recently, the melanocor-
tin 4 receptor (MC4-R) has been specifically identified as
a key modulator of appetite, body weight, and energy
homeostasis.2–11 Initial proof of concept reports have
demonstrated the reversal of anorectic conditions in
rodents via intracerebroventricular (icv) injection of
peptidic MC4-R antagonists.12–15 Additionally, MC4-R
knockout mice resist development of both LPS-induced
and cancer cachexia.16 Therefore, pharmacological
antagonism of the MC4-R is a potential therapy for the
treatment of involuntary weight loss.17–19 The identifi-
cation of MC4-R selective small-molecule ligands has
been an area of intense pharmaceutical research in re-
cent years,20–27 as has been recently reviewed.28–30 Con-
sequently, we have initiated an effort to identify small
molecule antagonists of the MC4-R with the goal of
developing therapeutically useful agents for the treat-
ment of involuntary weight loss due to advanced age or
disease (e.g. cancer or AIDS).
Our initial MC4-R antagonist optimization effort
examined a series of amidine-based small molecule
antagonists, which were developed from lead com-
pounds identified in a high throughput screen.31 An
antagonist identified in this effort (1, Fig. 1) exhibits
0.023 lM binding affinity and 0.30 lM functional
activity. Although a representative member of this series
(2, Fig. 1) efficiently penetrates the blood–brain barrier
Keywords: MC4-R; Melanocortin receptor; Antagonist.
* Corresponding author at present address: Department of Medicinal
Chemistry, Genomics Institute of the Novartis Research Foundation
(GNF), 10675 John Jay Hopkins Dr., San Diego, CA 92121, USA.
Tel.: +1-858-332-4604; fax: +1-858-812-1648; e-mail: tmarsilje@
gnf.org
Figure 1.
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.003

3722
T. H. Marsilje et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3721–3725
after sc or iv dosing in mice,31 2 demonstrates low oral
exposure when dosed in rat (Cmax ¼ 31 nM) and low iv
plasma levels (AUC ¼ 204 nM h) with rapid plasma
clearance (Cl ¼ 13.3 L/h/Kg).32 The focus of the current
study was to investigate a related series of compounds in
which the previously examined amidine moiety was
replaced by a series of imidazole ring systems. Initial
metabolite identification studies indicate that the ami-
dine ring system in the original antagonist series is
metabolized to the corresponding imidazole (Fig. 2).33
Therefore, the synthesis of a series of imidazole analogs
enables us to identify and characterize the biological
properties of proposed imidazole metabolites as well as
circumvent this metabolic pathway. Furthermore, we
hypothesized that reducing the basicity of the amidine
ring system may improve pharmacokinetic properties,
including oral exposure. The series of antagonists de-
scribed herein (Fig. 3) incorporate the optimized central
core phenyl ring (X ¼ H, F, Cl), ethylene linker, and
2-methoxy-5-bromo phenyl southern aromatic ring as
identified and described previously.31 This SAR study of
imidazole analogs examined the feasibility of replacing
the parent imidazoline ring system as well as imidazole
ring substituent effects.
Figure 3.
The synthesis of a series of N-substituted imidazole
analogs is shown in Scheme 1. The nitrile synthetic
intermediate31 was reacted with ethylene diamine in the
presence of H2S (neat, 100 ꢁC, 12 h). The imidazoline
34
produced was oxidized with BaMnO4 to the corre-
sponding imidazole 3 (CH2Cl2, reflux, 12 h). Imidazole 3
was alkylated with a series of alkyl halides under basic
conditions (NaH, DMF, 0 ꢁC) to generate analogs 4–9.
The syntheses of the fused c-pentyl and c-hexyl imi-
dazoles (11–14) followed a similar synthetic strategy
(Scheme 1). Commercially available 2-(aminomethyl)
pyrrolidine and 2-(aminomethyl) piperidine were
reacted with the appropriate nitrile synthetic interme-
diates in the presence of H2S (neat, 100 ꢁC, 1–3 d). The
resulting imidazoline intermediates were oxidized with
BaMnO4 to the corresponding imidazoles (11–14,
CH2Cl2, reflux, 1–3 d). The syntheses of imidazole ana-
logs 15–20 required a different synthetic strategy, as
shown in Scheme 2. o-Toluic acid was deprotonated
(2.1 equiv sec-BuLi, 2 equiv TMEDA, anhyd THF,
)78 ꢁC, 1 h) followed by alkylation with 5-bromo-2-
methoxy-benzyl bromide31 (1 equiv, anhyd THF,
)78 ꢁC, 1 h). The resulting carboxylic acid intermediate
was coupled with the appropriate amino alcohols35 uti-
lizing TFFH36 to form the corresponding hydroxy
Scheme 1.
amides. The hydroxy amide intermediates were cyclized
to the corresponding N-methyl imidazolines via reaction
with SOCl2, followed by sequential reaction with
Figure 2.

T. H. Marsilje et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3721–3725
3723
fused imidazoles do exhibit slightly enhanced functional
potency (0.39–0.71 lM) as compared to the imidazole
analogs (4–9), which were substituted only on the
nitrogen atom of the imidazole ring. Within this series of
imidazoles, the halogen substituent on the central core
phenyl ring (Cl vs F, analogs 11–14) was determined to
have little effect (<2 ·) upon both MC4-R binding
affinity and functional potency.
Finally, a series of N-methyl imidazoles (15–20) were
examined, which contain alkyl substituents in the 4 and/
or 5 positions of the imidazole ring. These analogs are
devoid of core phenyl ring halogens since these substit-
uents have negligible affects on MC4-R binding affinity
or functional potency.33 The addition of a methyl (15) or
ethyl (16) substituent in the 5-position (R2) of the
imidazole ring causes no change (<2 ·) in MC4-R
binding, as compared to the parent N-methyl imidazole
4. However, the addition of these alkyl substituents
significantly increases the functional potency of these
analogs by ca. 5–20 ·, compared to compound 4. The
1,5-dimethyl compound, 15, is the most potent imidaz-
ole antagonist identified in this study, with an
IC50 ¼ 0.051 lM. Similarly, the addition of a methyl
substituent at the 4-position (R3) of the imidazole ring
(17) enhances functional activity ca. 5-fold
(IC50 ¼ 0.24 lM) without changing MC4-R binding
affinity. The addition of an ethyl substituent in the 4-
position of the imidazole ring (18) significantly lowers
binding affinity and functional activity as compared to
the corresponding methyl-substituted compound 17.
This loss in binding affinity and functional potency is
even more significant in the case of the corresponding 5-
isopropyl analog 19 (Ki and IC50 both >1 lM), indicat-
ing that potential steric limitations exist at this portion
of the MC4-R binding pocket. The tri-methyl substi-
tuted imidazole, 20, exhibits 0.14 lM MC4-R binding
affinity and functional activity (0.20 lM), which is
within the standard deviation of the di-substituted
imidazole analogs (15–17).
Scheme 2.
methylamine (g) and 1 N NaOH (aq).37 Finally, the
imidazoline intermediates were oxidized with MnO2 to
the corresponding imidazoles (15–20, toluene, 80 ꢁC,
2 h).
The binding affinities and functional activities of agents
3–20 against the MC4-R are shown in Table 1. In
comparison with the parent imidazoline 1, the corre-
sponding imidazole 3 exhibits a ca. 65-fold decrease in
MC4-R binding affinity (1.5 lM vs 0.023 lM). However,
3 retains similar (<2 · difference) functional activity to
that of imidazoline 1 (0.58 lM vs 0.30 lM).
Initially, the biological activities of a series of N-alkyl-
ated imidazoles (4–9) were examined. Small alkyl sub-
stitutents on the nitrogen (e.g. Me (4) and Et (5)) result
in modest gains in MC4-R binding affinity (ca. 5 ·)
compared to the unsubstituted imidazole 3. The N-iso-
propyl substituted imidazole 6 exhibits a smaller
enhancement of binding affinity (ca. 2 ·). Larger N-
substituents (7–9) decrease binding affinity to micro-
molar levels, indicating potential steric constraints
within this portion of the MC4-R binding pocket. All
the N-substituted analogs discussed above exhibit
modestly reduced functional activities (ca. 1–2 lM),
compared to the parent imidazole (3).
The importance of the aromatic methyl ether in the
southern hemisphere to both MC4-R binding affinity
and functional activity is apparent via the comparison of
compounds 4 and 10 (Table 1). Phenol 10, obtained
from methyl ether 4 by means of reaction with BBr3,
exhibits a ca 30 · loss in binding affinity (9.3 lM) and
ca 9 · loss in functional potency (10.2 lM) as compared
to 4.
Improving the poor pharmacokinetics of the amidine
lead compound 2 was one of the motivations for
examining a series of imidazole replacements for the
amidine ring system. We hypothesized that this
replacement would circumvent a primary metabolic
pathway identified by initial metabolic studies (hetero-
cyclic ring hydroxylation followed by elimination). In
addition, we hypothesized that reducing the basicity
of the parent compound may improve oral exposure.
Upon iv dosing in rats (1 mg/kg), amidine 2 shows low
plasma levels and high clearance (AUC ¼ 204 nM h,
A series of 1,5-fused c-pentyl and c-hexyl imidazoles
(11–14) were examined. The MC4-R binding affinities of
these bicyclic analogs are similar to the N-methyl, N-
ethyl, and N-isopropyl analogs discussed above (0.18–
0.62 lM). This indicates that the fusion of additional
methylene subunits to the imidazole ring are sterically
accommodated, but do not affect binding affinity to the
MC4-R relative to N-substitution alone. However, these
Cl ¼ 13.3 L/h/Kg). In comparison,
a representative
imidazole (12) demonstrates increased iv plasma levels

3724
T. H. Marsilje et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3721–3725
Table 1. In vitro MC4-R binding affinity and functional potencya
Compounda
R1
R2
R3
X
Ar
MC4-R Binding MC4-R cAMP
Ki (lM)b
IC50 (lM)c
3
H
Me
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OH phenyl
1.5 0.3d
0.30 0.17
0.31 0.10
0.67 0.06
1.3 0.1
0.58 0.02
1.1 0.3
1.8 0.3
4
H
H
5
Et
H
H
6
i-Propyl
n-Propyl
sec-Butyl
CH2-c-propyl
Me
H
H
1.4 0.0
1.9 0.1
7
H
H
8
H
H
2.5 0.0
2.0 0.1
9.3 1.5
2.1 0.4
1.7 0.4
9
H
H
10
11
12
13
14
15
16
17
18
19
20
H
Fused c-pentyl
H
10.2 2.6
0.71 0.28
0.59 0.11
0.39 0.00
0.48 0.12
0.051 0.003
0.17 0.10
0.24 0.17
0.82 0.00
1.2 0.3
Fused c-pentyl
Fused c-hexyl
Fused c-pentyl
Fused c-hexyl
Me
H
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
5-Br-2-OCH3 phenyl
0.18 0.08
0.34 0.05
0.32 0.14
0.62 0.02
0.18 0.01
0.32 0.01
0.27 0.01
0.69 0.17
1.6 0.0
Fused c-hexyl
Fused c-pentyl
Fused c-hexyl
H
H
H
F
Me
Et
H
H
H
H
H
H
H
H
Me
Me
H
Me
Et
i-Propyl
Me
Me
Me
H
H
Me
Me
0.14 0.00
0.20 0.15
a All compounds demonstrated satisfactory LC–MS and 1H NMR characterization.
b MC4-R membrane filtration binding assay.
c Functional IC50 values were calculated by the compounds ability to decrease the intracellular cAMP level induced by 1 nM NDP-MSH in HEK293/
hMC4 cells.
d Standard deviation (n P 2).
2. Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Seeley,
R. J.; Baskin, D. G. Nature 2000, 404, 661.
(AUC ¼ 1998 nM h) and dramatically reduced plasma
clearance (Cl ¼ 1.1 L/h/Kg). In addition, upon po dos-
3. Lawrence, C. B.; Turnbull, A. V.; Rothwell, N. J. Curr.
ing in rats (5 mg/kg), imidazole 12 shows significantly
Opin. Neurobiol. 1999, 9, 778.
improved absolute oral exposure (Cmax ¼ 6454 nM) in
4. Cummings, D. E.; Schwartz, M. W. Nat. Genet. 2000, 26,
comparison to amidine 2 (Cmax ¼ 31 nM). Additional in
8.
vivo profiling of the disclosed imidazole series is neces-
5. Chen, A. S.; Metzger, J. M.; Trumbauer, M. E.; Guan, X.;
sary in order to determine if the initial observation of
dramatically improved pharmacokinetics over the ori-
ginal amidine series continues to be demonstrated.
Yu, H.; Frazier, E. G.; Marsh, D. M.; Forrest, M. J.;
Gopal-Truter, S.; Fisher, J.; Camacho, R. E.; Strack, A.
M.; Mellin, T. N.; MacIntyre, D. E.; Chen, H. Y.; Van der
Ploeg, L. H. T. Transgenic Res. 2000, 9, 145.
6. Marks, D. L.; Cone, R. D. Recent Prog. Horm. Res. 2001,
56, 359.
7. Forbes, S.; Bui, S.; Robinson, B. R.; Hochgeschwender,
U.; Brennan, M. B. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
4233.
8. Raffin-Sanson, M. L.; Bertherat, J. Eur. J. Endocrinol.
2001, 144, 207.
9. Poggiolo, R.; Vergoni, A. V.; Bertolini, A. Peptides 1986,
7, 843.
10. Lu, D.; Willard, D.; Patel, I. R.; Kadwell, S.; Overton, L.;
Kost, T.; Luther, M.; Chen, W.; Yowchik, R. P.;
Wilkinson, W. O.; Cone, R. D. Nature 1994, 371, 799.
11. Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dun-
more, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.;
Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith, F. J.;
Campfield, L. A.; Burn, P.; Lee, F. Cell 1997, 88, 131.
12. Vergoni, A. V.; Bertolini, A.; Wikberg, J. E. S.; Schioth,
H. B. Eur. J. Pharmacol. 1999, 369, 11.
In conclusion, a novel series of imidazole-based small
molecule antagonists of the MC4-R is reported. Mem-
bers of this class of compounds exhibit sub-micromolar
binding affinity and potently antagonize the MC4-R
with functional IC50 values <0.100 lM. The most potent
agent identified (15) antagonizes the MC4-R with a
functional IC50 ¼ 0.051 lM. Representative members of
the imidazole series were assayed against the MC1,
MC3, and MC5 receptors and they offer 1–2 orders of
magnitude selectivity for the MC4 receptor.33 As
hypothesized, a representative imidazole 12 demon-
strates improved pharmacokinetics and oral exposure as
compared to the earlier examined amidine 2.
Acknowledgements
13. Huang, Q.-H.; Hruby, V. J.; Tatro, J. B. Am. J. Physiol.
1999, 276, R864.
14. Lawrence, C. B.; Rothwell, N. J. J. Neuroendocrinol. 2001,
13, 490.
15. Wisse, B. E.; Frayo, R. S.; Schwarz, M. W.; Cummings,
D. E. Endocrinology 2001, 142, 3292.
We thank the Departments of Analytical Chemistry and
DMPK, and other MC4-R team members for helpful
discussions and contributions to this project.
16. Marks, D. L.; Ling, N.; Cone, R. D. Cancer Res. 2001, 61,
1432.
17. Inui, A. Cancer Res. 1999, 59, 4493.
References and notes
1. Wikberg, J. E. S. Exp. Opin. Ther. Patents 2001, 11, 61.
18. Lechan, R. M.; Tatro, J. B. Endocrinology 2001, 142, 3288.

T. H. Marsilje et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3721–3725
3725
19. Adan, R. A.; Vink, T. Eur. Neuropsychopharmacol. 2001,
11, 483.
Stearns, R. A.; Miller, R. R.; Tamvakopoulos, C.; Strack,
A. M.; McGowan, E.; Cashen, D. E.; Drisko, J. E.; Hom,
G. J.; Howard, A. D.; MacIntyre, D. E.; Van der Ploeg, L.
H. T.; Patchett, A. A.; Nargund, R. P. J. Med. Chem.
2002, 45, 4589.
20. Fotsch, C.; Smith, D. M.; Adams, J. A.; Cheetham, J.;
Croghan, M.; Doherty, E. M.; Hale, C.; Jarosinski, M. A.;
Kelly, M. G.; Norman, M. H.; Tamayo, N. A.; Xi, N.;
Baumgartner, J. W. Bioorg. Med. Chem. Lett. 2003, 13,
2337.
21. Arasasingham, P. N.; Fotsch, C.; Ouyang, X.; Norman,
M. H.; Kelly, M. G.; Stark, K. L.; Karbon, B.; Hale, C.;
Baumgartner, J. W.; Zambrano, M.; Cheetham, J.;
Tamayo, N. A. J. Med. Chem. 2003, 46, 9.
22. Ruel, R.; Herpin, T. F.; Iben, L.; Luo, G.; Martel, A.;
Mason, H.; Mattson, G.; Poirier, B.; Ruediger, E. H.; Shi,
D.; Thibault, C.; Yu, G.; Antal-Zimanyi, I.; Poindexter,
G. S.; Macor, J. E. Bioorg. Med. Chem. Lett. 2003, 13,
4341.
23. Richardson, T. I.; Ornstein, P. L.; Briner, K.; Fisher, M.
J.; Backer, R. T.; Biggers, C. K.; Clay, M. P.; Emmerson,
P. J.; Hertel, L. W.; Hsiung, H. M.; Husain, S.; Kahl, S.
D.; Lee, J. A.; Lindstrom, T. D.; Martinelli, M. J.; Mayer,
J. P.; Mullaney, J. T.; O’Brien, T. P.; Pawlak, J. M.;
Revell, K. D.; Shah, J.; Zgombick, J. M.; Herr, R. J.;
Melekhov, A.; Sampson, P. B.; King, C.-H. R. J. Med.
Chem. 2004, 47, 744.
24. Ujjainwalla, F.; Warner, D.; Walsh, T. F.; Wyvratt, M. J.;
Zhou, C.; Yang, L.; Kalyani, R. N.; MacNeil, T.;
VanderPloeg, L. H. T.; Rosenblum, C. I.; Tang, R.;
Vongs, A.; Weinberg, D. H.; Goulet, M. T. Bioorg. Med.
Chem. Lett. 2003, 13, 4431.
25. Dyck, B.; Parker, J.; Phillips, T.; Carter, L.; Murphy, B.;
Summers, R.; Hermann, J.; Baker, T.; Cismowski, M.;
Saunders, J.; Goodfellow, V. Bioorg. Med. Chem. Lett.
2003, 13, 3793.
27. Xi, N.; Hale, C.; Kelly, M. G.; Norman, M. H.; Stec, M.;
Xu, S.; Baumgartner, J. W.; Fotsch, C. Bioorg. Med.
Chem. Lett. 2004, 14, 377.
28. Foster, A. C.; Joppa, M.; Markison, S.; Gogas, K. R.;
Fleck, B. A.; Murphy, B. J.; Wolff, M.; Cismowski, M. J.;
Ling, N.; Goodfellow, V. S.; Chen, C.; Saunders, J.;
Conlon, P. J. Ann. N.Y. Acad. Sci. 2003, 994, 103.
29. Goodfellow, V. S.; Saunders, J. Curr. Top. Med. Chem.
2003, 3, 855.
30. Sebhat, I.; Ye, Z.; Bednarek, M.; Weinberg, D.; Nargund,
R.; Fong, T. M. Annu. Rep. Med. Chem. 2003, 38, 31.
31. Vos, T. J.; Caracoti, A.; Che, J. L.; Dai, M.; Farrer, C. A.;
Forsyth, N. E.; Drabic, S. V.; Horlick, R. A.; Lamppu, D.;
Yowe, D. L.; Balani, S.; Li, P.; Zeng, H.; Joseph, I. B. J.
K.; Rodriguez, L. E.; Maguire, M. P.; Patane, M. A.;
Claiborne, C. F. J. Med. Chem. 2004, 47, 1602.
32. Dosed 1 mpk (iv) and 5 mpk (po) in rats.
33. Data not shown.
34. Hughey, J. L.; Knapp, S.; Schugar, H. Synthesis 1980, 489.
35. (a) Commercially available; (b) Synthesized via reduction
of the corresponding commercially available amino acid
via the method of: Khayer, K.; Jenn, T.; Akhtar, M.;
John, R.; Gani, D. Tetrahedron Lett. 2000, 41, 1637; (c) 2-
Amino-3-hydroxy butane was synthesized by aminolysis
of commercially available 2,3-epoxybutane (satd NH3 in
CH3OH, 1 equiv H2O, 25 ꢁC, 72 h).
36. TFFH ¼ Tetramethylfluoroformamidinium hexafluoro-
phosphate. Carpino, L. A.; El-Faham, A. J. Am. Chem.
Soc. 1995, 117, 5401.
37. Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.;
Smyth, M. P. J. Org. Chem. 2002, 67, 3919.
26. Sebhat, I. K.; Martin, W. J.; Ye, Z.; Barakat, K.; Mosley,
R. T.; Johnston, D. B. R.; Bakshi, R.; Palucki, B.;
Weinberg, D. H.; MacNeil, T.; Kalyani, R. N.; Tang, R.;