Synthesis and structure-activity relationships of novel dipeptides and reduced dipeptides as ligands for melanocortin subtype-4 receptor

Article abstract of DOI:10.1016/j.bmcl.2005.10.103

A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-d-Tic-d-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.

Full text of DOI:10.1016/j.bmcl.2005.10.103

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2341–2346
Synthesis and structure–activity relationships of novel
dipeptides and reduced dipeptides as ligands for
melanocortin subtype-4 receptor
Qing Shi,* Paul L. Ornstein, Karin Briner, Timothy I. Richardson, Macklin B. Arnold,
Ryan T. Backer, Jennifer L. Buckmaster, Emily J. Canada, Christopher W. Doecke,
Larry W. Hertel, Nick Honigschmidt, Hansen M. Hsiung, Saba Husain, Steve L. Kuklish,
Michael J. Martinelli,ꢀ Jeffrey T. Mullaney, Thomas P. OꢁBrien, Matt R. Reinhard,
Roger Rothhaar, Jikesh Shah, Zhipei Wu, Chaoyu Xie,
John M. Zgombickꢂ and Matthew J. Fisher
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 8 September 2005; revised 28 October 2005; accepted 28 October 2005
Available online 15 November 2005
Dedicated to the memory of David W. Robertson in recognition of his outstanding accomplishments in drug discovery and research.
Abstract—A series of benzylic piperazines (e.g., 4 and 5) attached to an ꢃaddress elementꢁ, the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3
has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure–activity relation-
ship (SAR) studies on the N-terminal residue of the ꢃaddress elementꢁ. Several novel dipeptides and reduced dipeptides with high
MC4R binding affinities and selectivity emerged from this SAR study.
Ó 2005 Elsevier Ltd. All rights reserved.
The five melanocortin receptors (MCR) form a subfam-
ily of G-protein coupled receptors (GPCRs).1,2 The mel-
anocortins [e.g., adrenocorticotropic hormone (ACTH),
a-melanocyte-stimulating hormone (a-MSH), b-MSH,
and c-MSH] are agonist peptide ligands for these recep-
tors and they are derived from post-translational
processing of proopiomelanocortin (POMC).3 The mel-
anocortins and their corresponding receptors support
diverse physiological functions including feeding behav-
ior and erectile function.4–7
molecules can be described as being composed of a
GPCR privileged structure coupled to a dipeptide ꢃad-
dress elementꢁ as shown in Figure 1. We have reported
structure–activity relationships regarding the privileged
structures utilizing a fixed H-D-Tic-D-p-Cl-Phe-OH
dipeptide address element.9,10 While we have shown that
chemical modifications of the privileged structure can
provide significant dynamic range of biological activities
for these series, we wondered if modification of the ad-
dress element would provide additional opportunities
for increases in potency and modifications of overall
physicochemical properties.11 We herein report an effort
to develop new address elements focusing on the
replacements of the N-terminal residue.
Selective small molecule melanocortin agonists have
been reported by several research groups.7,8 We have
recently reported the identification of a series of novel
aryl and benzylic piperazines (e.g., 1 and 2), which have
potent and selective MC4R agonist activity.9,10 These
Syntheses of N-terminal residues derived from (2,3-dihy-
dro-1H-isoindol-1-yl)-acetic acid are described in
Scheme 1. Commercially available 2-bromobenzylamine
hydrochloride was protected with Boc2O to give inter-
mediate 7, which was then subjected to a Heck reaction
with methyl acrylate in the presence of TEA and a cat-
alytic amount of dichlorobis (triphenylphosphine) palla-
dium (II) to yield 8. Deprotection of 8 allowed the
Keywords: Melanocortin subtype-4 receptor ligands; MC4R.
*
Corresponding author. Tel: +1 317 277 9158; fax: +1 317 276 1417;
e-mail: shi_qing@lilly.com
Deceased.
ꢂ
ꢀ
Present address: Amgen Inc., One Amgen Center Drive, Thousand
Oaks, CA 91320, USA.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.103

2342
Q. Shi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2341–2346
N-Terminal Residue
Cl
Cl
O
O
O
N
O
H
N
H
OH
HN
N
N
HN
Dipeptide Address Element
H
N
3
N
N
X
X
N
X
MC4R Ki (nM)
1 Cl
2 F
10.5
14.1
Privileged Structure
4 X = Cl
5 X = F
Figure 1. Disconnective analysis of MC4R active leads.
of 12a or 12b was not elucidated; rather their identity
H
was tracked by their order of elution. Both enantiomers
12a and 12b were hydrolyzed with NaOH providing 13a
and 13b, respectively. Alternatively, enantiomers 12a
and 12b were each converted to the N-methyl derivatives
16a (isomer 1) and 16b (isomer 2), respectively, by
deprotection, reductive amination with formaldehyde,
and hydrolysis.
N
ii
boc
H
N
R1
R
R2
HCl
Br
O
O
8 R1 = H, R2 = Me
9 R1= Me, R2 = Et
6 R = H
7 R = boc
i
iii, iv
An example of a 1-methyl substituted isoindoline was
prepared in an analogous fashion starting from 7 and
ethyl crotonate. The racemic isoindoline 15 was then
coupled to D-p-Cl-Phe-OMe (26) as shown in Scheme
4. The resulting diastereomers were deprotected and sep-
arated by reversed-phase HPLC (elution: 90/10 to 65/35,
H2O/CH3CN over 30 min) to give 27a (isomer 1, first
eluting isomer) and 27b (isomer 2, second eluting
isomer). The diastereomers 27a and 27b were each pro-
tected and hydrolyzed to 28a and 28b, respectively.
v
1
O
R
1
O
R
NH
N
R2
R2
boc
O
O
12 R1 = H, R2 = Me
10 R1 = H, R2 = Me
11 R1 = Me, R2 = Et
vi
12a, 12b R1 = H, R2 = Me
13a, 13b R1 = H, R2 = H
14 R1 = Me, R2 = Et
vii
vii
15 R1 = Me, R2 = H
Preparation of N-terminal residues containing a tetrahy-
droisoquinoline moiety started from commercially avail-
able (1,2,3,4-tetrahydroisoquinolin-1-yl)-acetic acid 17
as outlined in Scheme 2. Ester formation and nitrogen
protection afforded 18 in good yield. This material was
separated into enantiomers 18a (isomer 1, first eluting
isomer; 100% ee) and 18b (isomer 2, second eluting iso-
mer; 100% ee) on a Chiralcel OD column (elution: 20/80,
IPA/heptane). Each enantiomer was then hydrolyzed
with LiOH to give 19a and 19b, respectively.
iii, viii, vii
O
O
N
N
boc
O
O
K
12a, 12b
16a, 16b
Scheme 1. Reagents: (i) K2CO3, t-Boc2O, THF/H2O (1:1); (ii)
CH2CHCOOMe (for 8) or CH3CHCHCOOEt (for 9), TEA,
(Ph3P)2PdCl2, DMF; (iii) TFA, CH2Cl2; (iv) NaHCO3, CH2Cl2; (v)
DIEA, t-Boc2O, CH2Cl2; (vi) Chiralcel OD column; (vii) 1 N NaOH,
MeOH or KOSi(Me)3, THF; (viii) 37% aq HCOH, NaB(OAc)3H, CH2Cl2.
i, ii
O
O
compound to undergo an intramolecular Michael addi-
tion affording isoindoline 10 as a racemic mixture, which
was then protected with Boc2O providing 12. The race-
mic mixture was resolved efficiently by chiral chroma-
tography with a Chiralcel OD column (elution: 10/90,
IPA/heptane) to give enantiomers 12a (isomer 1, first
eluting isomer; 100% ee) and 12b (isomer 2, second
eluting isomer; 99.0% ee). The absolute configuration
R
O
N
boc
HO
N
H
17
18, R = Me
18a, 18b R = Me
19a, 19b R = Li
iii
iv
Scheme 2. Reagents: (i) HCl, MeOH; (ii) t-Boc2O, THF; (iii) Chiralcel
OD column; (iv) LiOH, 1,4-dioxane/H2O.

Q. Shi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2341–2346
Cl
2343
O
O
HO
R
RO
ii
i, ii
O
O
O
+
NH2
NH
HO
O
NH2
N
O
boc
22 R = H
23 R = Tf
20 R = H
21 R = Et
i
iii
26
Cl
15
iv
O
O
R
O
N
O
N
R2
H
NH
O
R1
24 R = Et
25 R = Li
27 R1 = Me, R2 = H
v
iii
27a, 27b R1 = Me, R2 = H
28a, 28b R1 = H, R2 = boc
iv, v
Scheme 3. Reagents: (i) SOCl2, EtOH; (ii) acetone; (iii) Tf2O, TEA,
CH2Cl2; (iv) H2, 5% Pd/C, acetone/toluene; (v) LiOH, H2O, THF.
Cl
O
i
O
+
O
Li
HN
NH2
A 1,1-dimethyl substituted tetrahydroisoquinoline was
prepared as outlined in Scheme 3. Esterification of m-ty-
rosine 20 in the presence of thionyl chloride and ethanol
gave the ester 21, which was heated under reflux in ace-
tone to generate intermediate 22. The phenol was con-
verted to the corresponding triflate 23 with triflic
anhydride. Deoxygenation of this intermediate was
achieved catalytically with hydrogen in the presence of
5% Pd/C at 50 psi affording the desired intermediate
24. Hydrolysis of 24 with LiOH gave the lithium salt
25. The racemic mixture 25 was then coupled to D-p-
Cl-Phe-OMe (26). The resulting diastereomers 29 were
separated by flash chromatography (linear gradient,
40 ml/min 10–50% EtOAc/hexane for 25 min and 50%
EtOAc/hexane for 7 min) providing 29a (isomer 1, first
eluting isomer) and 29b (isomer 2, second eluting iso-
mer) as outlined in Scheme 4. Notable is the fact that
the nitrogen contained in these molecules is sufficiently
hindered as to preclude acylation under a variety of
standard conditions. Diastereomers 29a and 29b were
each hydrolyzed to 30a and 30b, respectively.
O
26
25
Cl
O
O
R
N
H
O
HN
29 R = Me
vi
v
29a, 29b R = Me
30a, 30b R = Li
Scheme 4. Reagents: (i) EDC, HOBT; (ii) TFA, CH2Cl2; (iii) HPLC;
(iv) t-Boc2O, CH2Cl2; (v) LiOH, THF, H2O or NaOH, MeOH;
(vi) flash chromatography.
O
O
ii
R
We also prepared an address element with an amine
linkage between the N-terminal residue and the
D-p-Cl-Phe instead of an amide linkage (Scheme 5).
Commercially available D-N-Boc-1,2,3,4-tetrahydro-iso-
quinoline-3-carboxylic acid 31 was converted to the
Weinreb amide 32 in the presence of EDC–HOBT. Lith-
ium aluminum hydride reduction gave the aldehyde 33,
which was then coupled to D-p-Cl-Phe-OMe (26) by
reductive amination. Hydrolysis of 34 with lithium
hydroxide provided the lithium salt 35, which was used
in the final peptide coupling without further protection
of the amino group.
H
N
N
boc
boc
31 R = OH
32 R = N (CH3)OCH3
33
i
Cl
iii
O
NH2
26
O
Cl
O
R
N
Since the resolved o-chloro and o-fluoro substituted
privileged structures 4 and 5 provided compounds with
good MC4R binding affinity (Fig. 1), they were chosen
for use in this report.10,12 Final compounds were pre-
pared as described in Scheme 6. The racemic mixture 4
was coupled with Boc-D-p-Cl-Phe-OH 36 and deprotec-
ted to give a mixture of diastereomers 37, which was fur-
ther coupled with 13a providing 40. Reversed-phase
H
N
O
boc
34 R = Me
35 R = Li
iv
Scheme 5. Reagents: (i) NH(Me)(OMe)ÆHCl, EDC, HOBT, DIEA,
THF; (ii) LiAlH4, THF; (iii) NaBH3CN, NaOAc, HOAc, MeOH; (iv)
LiOH, H2O/1,4-dioxane.

2344
Q. Shi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2341–2346
The final compounds either as TFA salt or HCl salt were
Cl
tested in a radioligand binding assay to determine the
competitive inhibition of 125I-NDP-a-MSH binding to
cloned human MC1, MC3, MC4, and MC5 receptors
using membranes from stably transfected HEK293
cells.9 The specific data obtained from the MC4R bind-
ing assay are listed in Tables 1–3 as well as Figure 1.
Cl
O
H
N
NH2
N
N
N
O
boc
N
H
N
OH
i, ii
36
N
We first chose to examine N-terminal modifications in
the o-Cl series 4 (Table 1). Replacement of the N-termi-
nal tetrahydroisoquinoline with an isomeric isoindoline
provided diastereomeric pairs 40a–b (178, 18 nM) and
41a–b (107, 5 nM). Consistent with previous observa-
tions, we found activity differences between privileged
structure antipodes.10 Comparing pairs 40a with 40b
and 41a with 41b demonstrates a 9- and 21-fold differ-
ence in affinity, respectively. It appears that the impact
on affinity of the N-terminal residue absolute configura-
tion was not as significant, evidenced by comparing 40b
(18 nM) with 41b (5 nM). We also observed similar
X
X
4 (racemate), X = Cl
4b (isomer 2), X = Cl
5b (isomer 2), X = F
37 X = Cl
38 X = Cl
39 X = F
Cl
Cl
O
NH2
N
O
N
O
N
H
N
H
N
N
N
N
37
Cl
Table 1. Chiral optimization on the N-terminal residue and privileged
structure
O
N
boc
Cl
i, ii
Cl
HO
40
40a, 40b
41
13a
13b
iii
iii
R
O
N
H
41a, 41b
N
N
Cl
N
O
NH2
N
N
Cl
Cl
Compound
R
MC4R Ki (nM)13
O
N
O
O
N
H
N
H
N
Cl
38
40a
177.8
O
HN
N
N
O
N
i, ii
O
boc
Li
Cl
40b
41a
18.1
HN
19a
19b
42
43
O
Scheme 6. Reagents: (i) EDC, HOBT; (ii) TFA, CH2Cl2; (iii) HPLC.
107.4
HN
O
HPLC separation of 40 (elution: 90/10 to 70/30, H2O/
CH3CN, 96 min) gave 40a (isomer 1, first eluting iso-
mer) and 40b (isomer 2, second eluting isomer). Similar-
ly, compounds 41a (isomer 1, first eluting isomer) and
41b (isomer 2, second eluting isomer) were prepared
from 13b and 37. Intermediate 38, generated from enan-
tiomer 4b (isomer 2)12, was coupled to 19a and 19b sep-
arately to provide 42 and 43, respectively. The rest of the
final compounds were prepared using EDC/HOBT or
HATU coupling and then TFA deprotection conditions.
Thus, 13b and 39 gave 44; 16b and 39 gave 45; 19a and
39 gave 46; 39 and commercially available isoquinoline-
3-carboxylic acid gave 47; 28a and 5b (isomer 2) gave 48;
30b and 5b gave 49; 35 and 5 (racemate) gave 50.
41b
42
5.3
HN
O
30.2
HN
O
43
6.4
HN

Q. Shi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2341–2346
2345
Table 2. SAR of the N-terminal residue
scribed in Table 2. Only the most active diastereomers
(in terms of affinity) are listed. Replacements of
tetrahydroisoquinoline carboxylic acid with (2,3-dihy-
dro-1H-isoindol-1-yl)-acetic acid and (1,2,3,4-tetrahy-
dro-isoquinolin-1-yl)-acetic acid again proved to be
successful, yielding compounds 44 (7 nM) and 46
(10 nM). a-Methylation of the isoindoline analog (48)
resulted in a 10-fold loss of MC4R binding affinity
relative to 44, which may indicate that steric bulk in this
position is not well tolerated. N-Methylation of (2,3-dihy-
dro-1H-isoindol-1-yl)-acetic acid (45) is tolerated provid-
ing an MC4R affinity of 17 nM, which is comparable to
that of the original tetrahydroisoquinoline analog 2.
Compound 49, possessing 1,1-dimethyl substitution on
the tetrahydroisoquinoline carboxylate residue, had good
MC4R binding affinity (6 nM). Replacing the tetrahydro-
Cl
R
O
N
H
N
N
N
F
Compound
R
MC4R Ki (nM)13
O
44
7.3
HN
isoquinoline moiety of
2 with isoquinoline gave
compound 47, which had reduced MC4R binding affinity
(96 nM). Reducing the amide linker of the dipeptide
address element found in 2 to the amine yielded 50, which
showed 40 nM binding affinity for MC4R.
O
45
46
47
48
49
50
17.3
10.4
95.6
73.7
5.8
N
O
All of the compounds listed in Table 2 showed good to
excellent selectivity for MC4R versus MC1R, MC3R,
and MC5R ranging from 10- to 1280-fold (Table 3).
HN
O
In summary, we have demonstrated that it is possible to
synthesize a variety of address elements containing a basic
nitrogen. Replacement of the N-terminal residue with the
less basic isoquinoline moiety caused an erosion of activ-
ity, which may indicate that the basic center provides a
positive interaction. Interestingly, the amide linker con-
tained in the dipeptide address element of 3 may not be re-
quired for activity as demonstrated by compound 50.
Several pairs of N-terminal enantiomers generated final
compounds with comparable MC4R binding affinity,
which provided the flexibility of using both R and S enan-
tiomers and it may provide more opportunities to change
physicochemical properties of the final compounds. Iden-
tification of these additional address elements, each with
their own unique physicochemical properties, should
facilitate the optimization of our privileged structure
based melanocortin ligands.
N
O
HN
O
HN
HN
40.6
Table 3. Binding affinity at hMC1R, hMC3R, hMC4R, and hMC5R13
Compound
MC1R
Ki (lM)
MC3R
Ki (lM)
MC4R
Ki (lM)
MC5R
Ki (lM)
Acknowledgments
44
45
46
47
48
49
50
6.0
8.6
3.0
7.0
20
3.4
4.6
4.2
1.4
16
0.0073
0.017
0.010
0.096
0.074
0.0058
0.041
1.2
2.0
The authors thank Mr. Xing-yue Zhang and Mr. Dennis
P. Smith for the MC4R binding assay.
0.91
0.92
1.4
7.0
5.8
1.9
7.0
0.42
0.95
References and notes
1. Cone, R. D. The Melanocortin Receptors; Humana:
Totowa, NJ, 2000, 209.
2. Cone, R. D.; Mountjoy, K. G.; Robbins, L. S.; Nadeau, J.
H.; Johnson, K. R.; Roselli-Rehfuss, L.; Mortrud, M. T.
Ann. N.Y. Acad. Sci. 1993, 680, 342.
3. Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dun-
more, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.;
Kesterson, R. A.; Boston, B.; Cone, R. D.; Smith, F. J.;
Campfield, L. A.; Burn, P.; Lee, F. Cell 1997, 88, 131.
4. Cone, R. D. The Melanocortin Receptors; Humana:
Totowa, NJ, 2000, 551.
results with the 1-substituted tetrahydroisoquinoline
acetic acid N-terminus, which provided analogs 42
(30 nM) and 43 (6 nM). The above data suggest that
each pair of N-terminal enantiomers provided final com-
pounds with comparable MC4R binding affinity.
Further examination of the address element SAR using
the o-fluoro substituted privileged structure 5 is de-

2346
Q. Shi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2341–2346
5. Vergoni, A. V.; Bertolini, A. Eur. J. Pharm. 2000, 405, 25.
6. Adan, R. A. H.; Gispen, W. H. Eur. J. Pharm. 2000, 405, 13.
Tucci, F. C.; Marinkovic, A. C.; Saunders, J. J. Med.
Chem. 2004, 47, 6821.
7. Herpin, T. F.; Yu, G.; Carlson, K. E.; Morton, G. C.; Wu,
X.; Kang, L.; Tuerdi, H.; Khanna, A.; Tokarski, J. S.;
Lawrence, R. M.; Macor, J. E. J. Med. Chem. 2003, 46,
1123.
9. 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.; OꢁBrien, 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.
10. Fisher, M. J.; Backer, R. T.; Collado, I.; Frutos, O. D.;
Husain, S.; Hsiung, H. M.; Kuklish, S. T.; Mateo, A.;
Mullaney, J. T.; Ornstein, P. L.; Paredes, C. G.; OꢁBrian,
T. P.; Richardson, T. I.; Shah, J.; Zgombick, J. M.; Briner,
K. Bioorg Med. Chem. Lett. 2005, 15, 4973.
11. For a related strategy, see Fotsch, C.; Han, N.; Arasas-
ingham, P.; Bo, U.; Carmouche, M.; Chen, N.; Davis, J.;
Goldberg, M. H.; Hale, C.; Hsieh, F.; Kelly, M. G.; liu,
Q.; Norman, M. H.; Smith, D. M.; Stec, M.; Tamayo, N.;
Xi, N.; Xu, S.; Bannon, A. W.; Baumgartner, J. W.
Bioorg. Med. Chem. Lett. 2005, 15, 1623.
12. Compounds 1 and 2 are enantiomerically pure. The
chiral chromatographic resolution of the chloro ana-
log 4 (giving 4a and 4b) was accomplished with the
same solvent system as reported for fluoro analog 5
in Ref. 10. The order of elution previously reported
for 5 was in error with the more active enantiomer
5b being the second eluting isomer, not the first (5a)
as reported.
8. (a) Pan, K.; Scott, M. K.; Lee, D. H. S.; Fitzpatrick, L. J.;
Crooke, J. J.; Rivero, R. A.; Rosenthal, D. I.; Vaidya, A.
H.; Zhao, B.; Reitz, A. B. Bioorg. Med. Chem. 2003, 11,
185; (b) 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.;
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; (c) Joseph, C. G.; Bauzo, R. M.; Xiang, Z.;
Haskell-Luevano, C. Bioorg. Med. Chem. Lett. 2003, 13,
2079; (d) 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; (e) Pontillo, J.; Tran, J.
A.; Arellano, M.; Fleck, B. A.; Huntley, R.; Marinkovic,
D.; Lanier, M.; Nelson, J.; Parker, J.; Saunders, J.; Tucci,
F. C.; Jiang, W.; Chen, C. W.; White, N. S.; Foster, A. C.;
Chen, C. Bioorg. Med. Chem. Lett. 2004, 14, 4417; (f)
Pontillo, J.; Tran, J. A.; Fleck, B. A.; Marinkovic, D.;
Arellano, M.; Tucci, F. C.; Lanier, M.; Nelson, J.; Parker,
J.; Saunders, J.; Murphy, B.; Foster, A. C.; Chen, C.
Bioorg. Med. Chem. Lett. 2004, 14, 5605; (g) Chen, C.;
Pontillo, J.; Fleck, A.; Gao, Y.; Wen, J.; Tran, J. A.;
13. All of Ki values reported here are an average from two or
four runs. Average error of the binding assay is 15%.