Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)

Article abstract of DOI:10.1016/j.bmcl.2008.09.015

A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.

Full text of DOI:10.1016/j.bmcl.2008.09.015

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5545–5549
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid
cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)
b
b
b
Kevin J. Moriarty c, Hidenori Takahashi a, , Steven S. Pullen , Hnin Hnin Khine , Rosemarie H. Sallati ,
Ernest L. Raymond b, Joseph R. Woska Jr. b, Deborah D. Jeanfavre b, Gregory P. Roth d, Michael P. Winters c,
Lei Qiao c, Declan Ryan c, Renee DesJarlais c, Darius Robinson c, Matthew Wilson c, Mark Bobko c,
Brian N. Cook a, Ho Yin Lo a, Peter A. Nemoto a, Mohammed A. Kashem a, John P. Wolak a, André White a,
Ronald L. Magolda a, Bruce Tomczuk c
*
a Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
b Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
c Johnson & Johnson, PRDUS, LLC, Springhouse, PA 19477, USA
d Burnham Institute for Medical Research at Lake Nona, Orlando, FL 32819, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2008
Revised 29 August 2008
Accepted 3 September 2008
Available online 7 September 2008
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared.
In this report, we discuss the structure–activity relationship (SAR), selectivity, and cell-based activity for
the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhib-
itors bound to ITK.
Ó 2008 Elsevier Ltd. All rights reserved.
This paper is dedicated to the memory of Dr.
Ronald L. Magolda.
Keywords:
SAR
Itk
Inhibitor
Benzimidazole
Antigen recognition by T-cells is the initiating stimulus for
T-cell activation. Activation of T-cells can lead to proliferation,
secretion of cytokines, and initiation of regulatory and cytolytic
effector functions. Engagement of the T-cell antigen receptor
(TCR) results in the rapid recruitment and activation of three
classes of non-receptor tyrosine kinases, the Src family (Lck and
Lyn), the Syk family (Zap-70 and Syk) and the Tec family (Itk,
Txk and Tec).1–3 Inhibiting any of these tyrosine kinases would
potentially impede T-cell activation following antigen presentation
by blocking the signaling cascade.4
are drastically reduced in response to challenge with the allergen
OVA.8 Together, these studies have defined an important role for
Itk in TCR signaling leading to thymic development and cytokine
gene expression.
In addition to the discovery of the role this kinase plays in this
important signaling pathway, Bristol–Myers Squibb (BMS) recently
disclosed a series of 2-amino-5-[(thiomethyl)aryl]thiazoles, exem-
plified by compound 1, which are potent and selective Itk inhibi-
tors.4,9 Compound 1 was shown to be effective at inhibiting IL-2
production in mice in
a dose dependent manner (50 and
IL-2 inducible T-cell kinase (Itk) is a key member of the Tec ki-
nase family and a number of factors point to the importance of this
kinase in immune disease. Deletion of Itk in mice results in re-
duced TCR-induced proliferation and reduced secretion of the cyto-
100 mpk, sc) following an intravenous injection of anti-CD3 anti-
body (Fig. 1).
Our interest in kinase-regulated approaches to inflammatory
diseases prompted us to evaluate the potential of Itk as a therapeu-
tic target. A screening program was initiated that identified com-
pound 2 as a hit structure. This compound was shown to be an
adenosine 50-triphosphate (ATP) competitive inhibitor of Itk, with
kines IL-2, IL-4, IL-5, IL-10 and IFN-c 5–7
Also, the immunological
.
symptoms of allergic asthma are attenuated in Itkꢀ/ꢀ mice and
lung inflammation, eosinophil infiltration and mucous production
an IC50 of 0.04 lM in the Itk kinase assay and an IC50 = 1.4 lM in
the DT40 cell-based assay.10 In this report, we discuss our initial
efforts in optimizing this series leading to potent and selective
* Corresponding author. Tel.: +1 203 798 5049; fax: +1 203 798 5297.
E-mail address: hidenori.takahashi@boehringer-ingelheim.com (H. Takahashi).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.015

5546
K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5545–5549
inhibitors of Itk in vitro with activity in reducing IL-2 production in
mouse and human cells.
against Itk, we explored replacements for the 2-thiophene ring. As
shown in Table 1, replacement of the 2-thiopene with 2-furyl, 5-
isoxazole, 3-pyridyl, or 4-pyridyl resulted in an improvement in
activity against Itk. Additionally, selectivity over IRK was also im-
proved. Similarly, a replacement of the 2-thiophene with a phenyl
ring (12) was also tolerated, albeit with only a small improvement
in IRK selectivity versus 2. We turned to substituent modifications
on the benzamide (Table 1). ortho-Substitution was found to be
The general synthetic route for the compounds is shown in
Scheme 1 and is illustrated with the preparation of 2. The commer-
cially available 4-fluoro-3-nitro-phenylamine (3) was acylated
with cyclohexanecarbonyl chloride in the presence of pyridine to
give 4. The secondary amide was then converted to the N-methyl
amide by alkylation with methyl iodide in the presence of NaH
at room temperature to give 5. The fluoride was displaced with
3-aminopropanamide at 50 °C overnight and the nitro group was
then reduced with NiCl2/NaBH4 in methanol to give the dianilino
compound 6 in quantitative yield.11 Compound 6 was treated with
cyanogen bromide, and the resulting 2-amino-1H-benzimidazole 7
was acylated with thiophene-2-carboxylic acid using PyBOP/DIEA
in DMF produced compound 2 in overall yield of 50%.
All compounds were screened for inhibitory activity against Itk
in a DELFIA assay.10 For determining selectivity, selected com-
pounds were also tested against the related kinases Tec, Bmx,
Txk, Btk as well as insulin receptor kinase (IRK), Syk and Lyn. Se-
lected compounds were tested for cellular activity by measuring
inhibition of Ca2+ flux in DT40 cells, and the inhibition of IL-2 pro-
duction in human and murine T-cells following TCR stimulation
with anti-CD3 antibody.
detrimental for activity (18, IC50 = 3.3 lM) while substitution at
the meta or para-positions proved to be the most beneficial. Small
electron-donating and withdrawing groups were well tolerated
showing little difference in Itk inhibitory activity. Increasing a size
at the para-position was not tolerated and lead to a loss in activity
with increasing size of the substituent. Carboxylic acid substitution
(25) at the para-position of the benzamide was also not tolerated
leading to a >100-fold loss in activity relative to compound 2.
Selectivity against IRK was also influenced by the substitution pat-
tern around the benzamide ring. The para-position (14, 15, 17 and
22) was found to be the preferred substitution yielding analogs
with >1000-fold selectivity. This same trend was also seen with
the pyridine analogs (8 vs 11). These results were consistent with
our previously proposed rationale for the improved selectivity of
the para-substituents. The improved selectivity results from a ste-
ric interaction with the gatekeeper residue (Met) at the opening of
the selectivity pocket of the insulin receptor kinase.10
Compound 2 had an IC50 = 0.04
a DT40 cell-based assay IC50 of 0.9
activity against Btk, Lyn and Syk, however, 2 showed activity
against IRK (IC50 = 0.14 M). In an effort to identify pharmaco-
lM in the Itk kinase assay with
lM). Compound 2 showed no
Having established the requirement for the benzamide substi-
tuent at the C-2 position of the benzimidazole, the SAR around
the benzimidazole N-1 position was explored. Table 2 summarizes
l
phores that would provide both improved selectivity and potency
4
O
3
N
5
N
O
S
NH
O
N
O
H
N
2
N
6
N
H
1
N
7
S
S
N
NH2
O
O
1
2
Figure 1. Structures of reported Itk inhibitors.
H
H2N
NO2
N
NO2
F
b
a
F
O
3
4
N
NH2
NH
N
NO2
F
O
c,d
O
5
6
O
NH2
O
S
N
N
N
N
N
N
NH2
NH
O
O
f
e
7
2
O
NH2
NH2
O
Scheme 1. Representative synthetic scheme for 2-amino-1H-benzimidazole class Itk inhibitors. Reagents and conditions: (a) cyclohexanecarbonyl chloride, pyridine, CH2Cl2,
0 °C–rt, 98%; (b) excess CH3I, NaH, THF, rt, 24 h, 94%; (c) 3-aminopropanamide, DIEA, CH3CN, 50 °C, 24 h, 85%; (d) NiCl2, NaBH4, CH3OH, rt, 24 h, 83%; (e) BrCN, EtOH, rt, 24 h,
88% (e) thiophene-2-carboxylic acid, PyBOP, DIEA, DMF, rt, 24 h, 86%.

K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5545–5549
5547
Table 1
Table 3
Effects of thiophene replacements on ITK inhibition
Importance of N–H group on C-2 for ITK inhibitory activity
O
O
O
N
CN
N
N
N
Cl
N
N
N
N
Ar
NH
CH2
O
NH
O
O
N
NH2
O
32
45
Compound
Ar
Itk IC50
(
l
M)
IRK IC50 (lM)
O
N
N
2
8
9
2-Thiophene
3-Pyridyl
5-Isoxazole
2-Furyl
4-Pyridyl
C6H5
C6H4(m-Br)
C6H4(p-Br)
C6H4(p-Cl)
C6H4 (m-OCH3)
C6H4 (p-OCH3)
C6H4(o-CH3)
C6H4(m-CH3)
C6H4(p-CH3)
C6H4 (m-CN)
C6H4 (p-CN)
C6H4(p-COCH3)
C6H4(p-CO2CH3)
C6H4(p-CO2H)
C6H4(p-CONH2)
C6H4(p-CONH(CH3))
0.040
0.005
0.010
0.010
0.025
0.016
0.009
0.003
0.004
0.010
0.012
3.3
0.056
0.035
0.004
0.004
0.068
0.25
0.140
0.850
1.8
0.55
4.9
CN
N
N
N
N
NH2
NH
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
O
O
0.235
0.095
H2N
H2N
>10
3.9
0.550
>10
NT
0.550
>10
0.125
l
M
M
M
22
46
l
Compound
Itk IC50 (lM)
32
45
22
46
0.006
>20
0.004
>20
l
>10
>10
NT
l
l
M
M
4.5
0.52
>10
NT
NT
NT
activity. Shortening the spacer length between the N-1 of the benz-
imidazole and the side chain primary amide (22 vs 37) resulted in
an 18-fold loss in potency while mono and di-substitution of the
amide NH2 of 22 resulted in a small loss in potency (2- to 4-fold).
Replacement of the propyl amide group in compound 22 with po-
lar groups was allowed with the proper spacer length (41 vs 42).
The 1-(3-methoxypropyl) (36, IC50 = 0.016
perazin-1-yl)propan-1-one (44, IC50 = 0.018
good activity albeit with a small loss in potency in comparison to
compound 22. The 3-(1H-imidazol-1-yl)propyl (40, IC50
0.004 M), 3-(4-methylpiperazin-1-yl)propyl (42, IC50 = 0.005 M)
and the (piperazin-1-yl)propan-1-one (43, IC50 = 0.005 M) ana-
the SAR observed for substitution on the N-1 position. Substitution
of the N-1 with linear alkyl groups lead to a 17-fold improvement
in potency going from a methyl (28, IC50 = 0.27
IC50 = 0.016 M) but extension of the chain to heptyl (30,
IC50 = 4.5 M) resulted in a 17-fold loss in activity relative to com-
pound 28. The N-iso-propyl analog (31) indicated that the -substi-
tution was tolerated at the N-1 position. Replacement of the
N-alkyl group with a phenethyl group (32, IC50 = 0.006 M) led to
lM) to a butyl (29,
l
M) and (4-methylpi-
l
lM) groups showed
l
a
=
l
l
l
l
an additional improvement in potency, however, substitution of
the phenyl ring (33–35) was not tolerated and lead to a loss in
logs on the other hand all had potencies similar to compound 22.
The importance of the C-2 amide linkage was also explored
(Table 3). Removal of the N–H group at C-2 (45, IC50 = >20 lM) re-
Table 2
sulted in a complete loss in activity. Although right hand side sub-
stituents of the molecules (32 and 45) are not identical, we can
make an activity comparison since p-Cl and p-CN phenyl showed
comparable ITK inhibitory activity (Table 2, compound 15 vs 22).
Similarly, complete removal of the carboxy aryl portion (46,
SAR of N-1 substituents on ITK inhibition
O
N
CN
N
N
NH
O
IC50 = >20 lM) was found to be equally detrimental to the activity
R1
against Itk. The results indicated that the amide connection be-
tween the benzimidazole and the aromatic groups is critical for
Itk inhibition.
Compound
R1
Itk IC50 (lM)
28
29
30
31
32
33
34
35
36
37
22
38
39
40
41
42
43
44
CH3
0.27
0.016
4.5
0.035
0.006
0.089
0.69
The SAR around the amide linkage on C-2 provided some insight
into the possible binding mode of these inhibitors to Itk. The loss of
activity associated with a removal of either the amide N–H or car-
bonyl suggested an involvement in hydrogen bonding to the hinge
region of the kinase. Two binding modes were envisioned; through
the amide linkage A or through its tautomer B (Fig. 2). In binding
mode A the N-1 substituent is oriented toward the solvent exposed
region while in B the N-1 group is pointing toward the ribose pock-
et. The SAR of the phenethyl analogs appeared to indicate a poten-
tial size restriction consistent with the later binding mode. This
hypothesis was confirmed by X-ray crystallography. A crystal
structure of compound 2 bound to Itk was solved and showed
the inhibitor adopting binding mode B (Fig. 3). The crystal struc-
ture of the 2/Itk complex reveals that 2 binds to the protein in
the same manner as binding mode B with the N-1 group situated
(CH2)3CH3
(CH2)6CH3
CH (CH3)2
CH2CH2C6H5
CH2CH2C6H4(p-OCH3)
CH2CH2C6H4(o-OCH3)
CH2CH2C6H3(2,4-di-Cl)
CH2CH2CH2OCH3
–CH2CONH2
–CH2CH2CONH2
–CH2CH2CONH(CH3)
–CH2CH2CON(CH3)2
3-(1H-Imidazol-1-yl)propyl
2.0
0.016
0.073
0.004
0.009
0.014
0.004
0.061
0.005
0.005
0.018
2-(4-Methylpiperazin-1-yl)ethyl
3-(4-Methylpiperazin-1-yl)propyl
(Piperazin-1-yl)propan-1-one
(4-Methylpiperazin-1-yl)propan-1-one

5548
K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5545–5549
R2
O
R2
O
H
N
H
N
hinge region
hinge region
N
H
N
H
R1
O
H
R3
R1
O
R3
H
N
O
O
R
N
N
N
N
N
R
A
B
Figure 2. Proposed binding modes to Itk.
Table 5
SAR of C-5 substituents on Itk inhibition
O
X
CN
N
N
R
NH
NH2
O
Compound
R
X
Itk IC50 (lM)
22
49
50
51
52
53
54
55
56
Cyclohexyl-CO–
CH3CO–
Ethyl-CO–
N
N
N
N
N
N
N
N
CH
0.004
0.059
0.32
iso-Propyl-CO–
0.22
Cyclopropyl-CO–
Cyclobutyl-CO–
Phenyl-CO–
–H
0.046
0.008
0.020
0.076
0.003
Figure 3. X-ray structure of compound 2 bound to Itk.
Cyclohexyl-CO–
in the ribose site of the ATP pocket (Fig. 3).12,13 The carbonyl of the
C-2 amide makes a hydrogen bond with the N–H of Met438 while
the N-3 makes a hydrogen bond interaction through the tauto-
meric form to the carbonyl of the Met438.
Our investigation moved next to the C-5 position of the benz-
imidazole ring. Introduction of an ethyl group at the R position
sulted in
IC50 = 0.008
a
loss in potency while the cyclobutyl ring (53,
lM) gave potency comparable to 22. Substituting the
cyclohexyl ring with a phenyl (54, IC50 = 0.020
pound with 5-fold less activity than compound 22, while removal
of the carboxy cyclohexyl group (55, IC50 = 0.076 M) led to a 19-
fold decrease in potency relative to compound 22. Interestingly,
replacement of the amide N with C–H (56, IC50 = 0.003
not attenuate the activity (Table 5).
lM) gave a com-
l
(47, IC50 = 0.007
activity, however when the methyl group (22, IC50 = 0.004
was replaced by an iso-propyl group (48, IC50 = 0.153
l
M) did not negatively impact the enzymatic
M)
M) there
lM) did
l
l
was a 38-fold loss in activity (Table 4).
Table 6
Replacement of the cyclohexyl ring with
IC50 = 0.059 M), ethyl (50, IC50 = 0.32 M) or iso-propyl (51,
IC50 = 0.22 M) resulted in a loss in potency. Replacement of the
a methyl (49,
Enzyme selectivity of selected Itk inhibitors
l
l
l
Compound
Lyn
IRa
Btka
Syka
Bmxa
Txka
Teca
cyclohexyl ring with a cyclopropyl (52, IC50 = 0.046
l
M) also re-
15
40
47
>1000
>1000
>1000
>1000
>1000
>1000
>500
>1000
520
>1000
>1000
>1000
>1000
>1000
>1000
550
85
77
>1000
>1000
>1000
a
Selectivity ratio IC50/IC50 Itk.
Table 4
Modification of N-substitution on C-5 position
Table 7
Human liver microsomal stability results of selected compounds
R
N
O
NH
CN
N
N
O
R
N
Ar
N
N
O
NH
O
R1
NH2
O
Compound
R
R1
Ar
HLM CLH
(% QH)
Compound
R
Itk IC50 (lM)
15
40
Cyclohexyl
Cyclohexyl
–CH2CH2CONH2
3-(1H-imidazol-1-yl)
propyl
p-Cl phenyl
p-CN phenyl
91
93
22
47
48
Me
Et
iso-Propyl
0.004
0.007
0.15
57
4-diF cyclohexyl
–CH2CH2CONH2
p-CN phenyl
19

K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5545–5549
5549
Having identified a series of potent inhibitors of Itk, a set of ana-
logs were profiled against a panel of other kinases (Table 6). Com-
microsome stability and leading to an orally active Itk inhibitor
will be presented in forthcoming publications.
pounds 15, 40 and 47 (Itk, IC50 = 0.004, 0.004 and 0.007 lM,
respectively) showed 77- to 1000-fold selectivity against all the ki-
nases screened.
References and notes
1. Kane, L. P.; Lin, J.; Weiss, A. Curr. Opin. Immunol. 2000, 12, 242.
2. Samelson, L. E. Annu. Rev. Immunol. 2002, 20, 371.
3. Ohashi, P. S. Nat. Rev. Immunol. 2002, 2, 427.
4. Lin, T. A.; McIntyre, K. W.; Das, J.; Liu, C.; O’Day, K. D.; Penhallow, B.; Hung, C.
Y.; Whitney, G. S.; Shuster, D. J.; Yang, X.; Townsend, R.; Postelnek, J.; Spergel, S.
H.; Lin, J.; Moquin, R. V.; Furch, J. A.; Kamath, A. V.; Zhang, H.; Marathe, P. H.;
Perez-Villar, J. J.; Doweyko, A.; Killar, L.; Dodd, J. H.; Barrish, J. C.; Wityak, J.;
Kanner, S. B. Biochemistry 2004, 11056.
Based on the enzyme activity and selectivity, compounds 15
and 40 were selected for further evaluation. Inhibitors 15 and 40
both showed good activity in the DT40 cell-based Ca2+ flux inhibi-
tion assay with IC50s of 0.32 and 0.51
15 inhibited anti-CD3 antibody induced IL-2 secretion both in mur-
ine TH1 cells (IC50 = 0.44 M) and splenocytes (IC50 = 0.52 M).
lM, respectively. Compound
l
l
5. Liao, X. C.; Littman, D. R. Immunity 1995, 757.
Compound 15, however, only weakly inhibited anti-CD3/anti-
CD28 antibody induced IL-2 secretion in human CD4+ T-cells
6. Schaeffer, E. M.; Debnath, J.; Yap, G.; McVicar, D.; Liao, X. C.; Littman, D. R.;
Sher, A.; Varmus, H. E.; Lenardo, M. J.; Schwartzberg, P. L. Science 1999, 284,
638.
7. Miller, A. T.; Wilcox, H. M.; Lai, Z.; Berg, L. J. Immunity 2004, 21, 67.
8. Forssell, J.; Sideras, P.; Eriksson, C.; Malm-Erjefalt, M.; Rydell-Tormanen,
K.; Ericsson, P. O.; Erjefalt, J. S. Am. J. Respir. Cell Mol. Biol. 2005, 32,
511.
9. Das, J.; Liu, C.; Moquin, R. V.; Lin, J.; Furch, J. A.; Spergel, S. H.; Doweyko, A. M.;
McIntyre, K. W.; Shuster, D. J.; O’Day, K. D.; Penhallow, B.; Hung, C. Y.; Kanner,
S. B.; Lin, T. A.; Dodd, J. H.; Barrish, J. C.; Wityak, J. Bioorg. Med. Chem. Lett. 2006,
16, 4148.
10. (a) Kashem, M. A.; Nelson, R. M.; Yingling, J. D.; Pullen, S. S.;
Prokopowicz, A. S., III; Jones, J. W.; Wolak, J. P.; Rogers, G. R.;
Morelock, M. M.; Snow, R. J.; Homon, C. A.; Jakes, S. J. Biomol. Screen.
2007, 12, 70; (b) Snow, R. J.; Abeywardane, A.; Campbell, S.; Lord, J.;
Kashem, M. A.; Khine, H. H.; King, J.; Kowalski, J. A.; Pullen, S. S.; Roma,
T.; Roth, G. P.; Sarko, C. R.; Wilson, N. S.; Winters, M. P.; Wolak, J. P.;
Cywin, C. L. Bioorg. Med. Chem. Lett. 2007, 17, 3660.
(IC50 = 4.1
l
M). Compound 40 inhibited IL-2 secretion in human
M) and murine TH1 cells (IC50 = 0.35 M).
CD4+ T-cells (IC50 = 0.65
l
l
Compounds 15 and 40 were tested using human microsomes
and both were found to be rapidly metabolized. Metabolite identi-
fication studies showed that the major metabolite was hydroxyl-
ation at the 4-position of the cyclohexyl ring. Introduction of
gem-difluorides (57) at the 4-position resulted in a dramatic
improvement in microsome stability and identified the cyclohexyl
ring as the major liability of the series (Table 7).
In summary starting from a screening hit with moderate en-
zyme activity and poor cellular potency, we optimized the series
using a systematic SAR approach leading to the identification of
novel potent and selective Itk inhibitors. The obtained X-ray struc-
ture suggested that the inhibitors bind to the kinase through an ex-
tended tautomeric intermediate. Microsome studies showed that
the cyclohexyl ring was the major site of metabolism and modifi-
cation of the ring lead to an increased stability. Further improve-
ments and modifications of the series focusing on improving the
11. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
12. Bentzien, J. M.; Farmer, B., II; Pullen, S. S.; Studts, J. M.; White, A. WO
2005066335 A1 2005: 356 or X-ray crystallographic information.
13. White, A.; Abeywardane, A.; Cook, B. N.; Fuschetto, N.; Gautschi, E.; John, A.;
Kroe, R. R.; Kronkaitis, A.; Li, Xiang; Pullen, S. S.; Roma, T.; Moriarty, K. J.; Roth,
G. P.; Snow, R. J.; Studts, J. M.; Takahashi, H.; Farmer, B. T., II, J. Biol. Chem.,
submitted for publication.