Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres

Article abstract of DOI:10.1016/j.bmcl.2014.01.011

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.

Full text of DOI:10.1016/j.bmcl.2014.01.011

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1062–1066
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2:
Development of a [3.3.0]-based series and other piperidine
bioisosteres
Douglas J. Sheffler a,b,e, , Michael T. Nedelovych a,b, Richard Williams b,g, , Stephen C. Turner f,
Brittany B. Duerk f, Megan R. Robbins f, Sataya B. Jadhav b, Colleen M. Niswender a,b,c, Carrie K. Jones a,b
,
a,b,c,d,
P. Jeffrey Conn a,b,c, R. Nathan Daniels a,f, , Craig W. Lindsley
⇑
⇑
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
c Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA
d Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
e Apoptosis and Cell Death Research Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd.,
La Jolla, CA 92037, USA
f Department of Pharmaceutical Sciences, Lipscomb University, College of Pharmacy and Health Sciences, Nashville, TN 37024-3951, USA
g Centre for Cancer Research and Cell Biology, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a
scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position.
Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free frac-
tion, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this
novel series and a number of other piperidine bioisosteric cores.
Received 12 December 2013
Revised 2 January 2014
Accepted 6 January 2014
Available online 13 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
GlyT1
Scaffold hopping
Transporter
Schizophrenia
Scaffold hopping has emerged as an attractive approach to rap-
idly access new chemical space and enable fast-follower programs
without the need for expensive and time-consuming HTS cam-
paigns.1–4 As the negative symptom cluster in schizophrenia re-
mains a critical unmet medical need,5–7 and GlyT1 inhibition has
been shown to be affective toward negative symptoms in Phase
II clicnial trials,8–14 we initiated scaffold hopping efforts to expedi-
ently develop novel GlyT1 inhibitors within a crowded intellectual
property (IP) space. In a recent Letter, we reported on our prelimin-
ary scaffold hopping exercise (Fig. 1) employing GlyT1 inhibitors
from Merck and Pfizer, 1 and 2, respectively, that generated a no-
vel, patented series exemplified by 3.15 Notably, 3 was a potent
GlyT1 inhibitor with an exceptional DMPK profile, high CNS pene-
tration and robust efficacy in preclinical models of schizophrenia.15
Based on work from our labs with mGlu1 NAMs, and the ability
of [3.3.0] systems, such as the octahydropyrrolo[3,4-c]pyrrole, to
effectively mimic piperazines,16 we focused our attention on the
potential bioisoteric replacement of the [3.1.0] system of 2 and 3,
as well as the piperidine of 1, with a [3.3.0] system, an octahydro-
cyclopenta[c]pyrrole, 5, and effectively scaffold hop from analogs 4
(Fig. 2). If successful at maintaining GlyT1 inhibitory activity, this
O
CF3
N
N
Cl
F
N
H
O
O
Cl
H
H
N
N
H
N
S
Cl
O
O
N
S
H
H
O
O
N
N
N
1
2
3
⇑
GlyT1 IC50 = 26 nM
GlyT1 IC50 = 11.6 nM
Corresponding authors.
E-mail addresses: nate.daniels@lipscomb.edu (R.N. Daniels), craig.lindsley@
GlyT1 IC50 = 5 nM
vanderbilt.edu (C.W. Lindsley).
Current address.
Figure 1. Reported GlyT1 inhibitors 1 (Merck) and 2 (Pfizer), and the novel series 3
(VU0240391), derived from scaffold hopping.
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2014.01.011

D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1062–1066
1063
O
(Scheme 1). Commercial racemic, 90% cis-benzylhexahydrocyclo-
penta[c]pyrrol-4(2H)-one 6 was subjected to hydrogenation condi-
tions to deprotect the benyl moiety in the presence of Boc2O to
provide 7. Conversion of the ketone to the oxime, followed by
‘Raney’ nickel reduction generated the racemic primary amine 8,
which was subsequently acylated with a variety of benzoyl
chlorides to deliver analogs 9. Finally, the Boc moiety was removed
with HCl, and the secondary pyrrolidine nitrogen capped with
various sulfonyl chlorides to afford analogs 10.
H
N
Ar
N
H
H
Ar
H
H
O
H
scaffold
hop
N
S
N
S
O
O
O
O
N
N
N
N
4
5
Initially, we held the 2,4-dichlorobenzamide constant and sur-
veyed a wide-range of sulfonamides in analogs 11 (Table 1). Unlike
the piperdine 1 and [3.1.0] series 3, few sulfonamide moieties were
tolerated. Ethyl (11a) and propyl congeners (11b) that were very
potent in the piperidine series 1, afforded inactive compounds
Figure 2. Envisioned scaffold hopping from the novel series 4 to a [3.3.0]-core, an
octahydrocyclopenta[c]pyrrole, 5 .
O
NH2
O
b,c
a
H
H
H
H
H
H
(GlyT1 IC50 > 10 lM). Aryl and heteroaryl analogs, such as 11d–
N
N
N
11f, were also devoid of GlyT1 activity. Only the N-methyl imidaz-
ole (11g) and the N-methyl triazole (11h) derivative were active,15
both displayed low nanomolar potency (GlyT1 IC50s of 25 nM and
15 nM, respectively) and were selective versus GlyT2 (IC50 > 30 -
Boc
Boc
Bn
6
7
8
H
N
H
N
Ar
Ar
lM). Based on the disposition previously noted for the N-methyl
d
e,f
H
H
H
H
O
O
imidazole sulfonamide in 3, we prepared a second library held
the N-methyl imidazole sulfonamide moiety constant, and sur-
veyed a broader range of amides in analogs 12 (Table 2).
N
N
S
R
Boc
O
O
The SAR was far more shallow than in the case of 3,15 with the
2,4-dichlorobenzamide (11g/12a) possessing optimal potency.
Other analogs such as the 2-triflouromethylbenzamide (12b) and
the 2-chlorobenzamide (12c) were respectable, with GlyT1 IC50s
of 112 6 nM and 115 18 nM, respectively. The vast majority of
other substitution patterns afforded a considerable loss in potency
9
10
Scheme 1. Reagents and conditions: (a) Boc2O, Pd(OH)2/C, H2 (50 psi), EtOH, rt; (b)
NH2OH, MeOH, 100 °C; (c) ‘Raney’ Ni, H2 (50 psi), rt; (d) ArCOCl, DIEPA, CH2Cl2, 0 °C;
(e) 4 N HCl/dioxane, rt; (f) RSO2Cl, DIEPA, CH2Cl2, rt. Overall yields range from
10–34%.
(GlyT1 IC50s from 631 nM to 10 lM), as did a cyclohexyl amide
congener 12l (GlyT1 IC50 = 617 nM). To ensure that the major
structural change in scaffold hopping from 1 to 3 to 12 did not alter
the competitive mechanism of action of GlyT1 inhibition, we
evaluated the affect of 12b on enzyme kinetics of [14C]-glycine
transport. As shown in an Eadie–Hoffstee plot (Fig. 3), this [3.3.0]
series, represented by 12b, competitively inhibits the enzyme
kinetics of [14C]-glycine transport. Thus, this series is competitive
would represent a major strucutral change, eliminating the pen-
dant cyclopropylmethyl moeity while introducing an additional
chiral center (providing an opportunity for enantioselective
activity).
Synthetically, analogs 10 were initially prepared as racemates
via
a
six step route that proceeded in ꢀ22% overall yield
Table 2
Table 1
Structures and activities of analogs 12
Structures and activities of analogs 11
H
Cl
N
Ar
H
N
H
H
O
H
H
O
Cl
N
S
N
S
R
O
O
O
O
N
N
11
12
a
a
Compound
R
GlyT1 IC50
(
lM)
GlyT2 IC50 (lM)
a
a
Compound
R
GlyT1 IC50
25
(
lM)
GlyT2 IC50
>30
(lM)
11a
11b
11c
>10
>10
>10
>30
>30
>30
12a
(11g)
12b
12c
12d
12e
12f
12g
12h
12i
2,4-diClPh
2-CF3PH
2-ClPh
2,4-diFPh
2,6-diFPh
2-FPh
3-FPh
4-FPh
3,4-diFPh
4-ClPh
3,4-diClPh
112b
115b
926
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
11d
11e
11f
>10
>10
>10
>30
>30
>30
631
1815
>10,000
2215
1569
1029
891
N
S
N
12j
12k
11g
11h
0.025
0.015
>30
>30
N
N
12l
617
>30
N
N
a
IC50s represent single determinations performed in duplicate.
The average of four determinations performed in duplicate.
a
b
IC50s represent single determinations performed in duplicate.

1064
D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1062–1066
Cl
Cl
O
O
Cl
Cl
NH
NH
H
H
O
N
O
N
N
O
N
O
H
H
S
S
N
N
20b
20a
(3aS,4S,6aR)
GlyT1 IC50 >10 µM
(3aR,4R,6aS)
GlyT1 IC50 = 433 nM
Figure 4. Structures and activities of cis-(3a,6a)-enantiomers 20a and 20b.
H
O
OH
O
R1
R1
N
R2
a,b
c-e
O
n
n
n
n
n
n
N
N
N
Boc
Boc
Boc
21, n = 1
23, n = 1
25, n = 1
22
24
, n = 2
, n = 2
26
, n = 2
H
N
R1
R1
f,g
O
27, n = 1
28
n
n
N
, n = 2
O
S
O
R3
Scheme 3. Reagents and conditions: (a) N,O-dimethylhydroxylamine, EDC, HOBt,
DIPEA, DMF, rt; (b) Ar(Het)MgX or R1MgX, THF, À78 °C; (c) NH2OH, MeOH, 50 °C;
(d) Raney Ni, H2, (45 psi), MeOH; (e) RCOCl, DIEPA, CH2Cl2, rt; (f) 4 N HCl, dioxane,
rt; (g) RSO2Cl, DIEPA, CH2Cl2, rt.
Figure 3. (A) Saturation [14C]-glycine transport in the presence of vehicle (red
squares) or 120 nM 12b (blue triangles). (B) An Eadie–Hoffstee diagram for 12b and
[
14C]-glycine.
(fu = 8.1%), clean CYP profile (IC50s > 10 lM), and reasonable micro-
with respect to glycine, in accordance with the known mechanism
of action for 1–3.15,17–20
Racemic 12a, the most potent of the [3.3.0]-series, possessed a
favorable DMPK profile, with a good unbound fraction in rat
somal stability (30% remaining at 90 min in fortified rat liver
microsomes). An oral plasma:brain level (PBL) study with oral dos-
ing (10 mg/kg p.o. in 0.5% methocellulose) of 12a afforded a low
BrainAUC:PlasmaAUC of 0.15. This preliminary data was encourag-
O
O
S
S
O
N
N
H
Si
N
H
a
b
O
N
N
H
N
H
13
racemic cis-14
(3aS,6aR)-15
(3aR,6aS)-15
O
O
S
Ar
NH2
H
NH
H
NH
H
c
d
e
N
N
H
N
H
H
16
17
18
O
Ar
O
NH
Ar
H
NH
f
g
H
O
N
N
H
S
NH
H
O
N
19
20a
Scheme 2. Reagents and conditions: (a) cyclopentenone, TFA, CH2Cl2, 0 °C, 16 h; (b) (R)-tert-butylsulfinamide, Ti(OEt)4, THF, 0 °C, 16 h, chromatographic separation of
diastereomers; (c) NaBH4, MeOH, À78 °C to rt, 3 h; (d) 2 N HCl (aq), MeOH, rt, 16 h; (e) ArCOCl, CH2Cl2, rt, 16 h; (f) chloroethyl chloroformate, Et3N, ClCH2CH2Cl, MeOH, rt,
20 h; (g) N-methyl imidazole sulfonyl chloride, Et3N, CH2Cl2, rt, 12 h. Overall yields range 5–22%.

D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1062–1066
1065
ing, and since 12a was a racemate (90% cis at the bridgehead), and
thus a mixture of 8 compounds, we then attempted to separate the
mixture by chiral SFC. We were able to separate three peaks off the
1–3, 12 and 20. Thus, chemistry was quickly developed to access
these cores (Scheme 3). Starting from commercially available N-
Boc-azetidine-3-carboxylic acid 21 or N-Boc-piperidine-4-carbox-
ylic acid 22, conversion to the Weinreb amide and treatment with
an aryl, heteroaryl or aliphatic Gringard reagent provided 23 and
24, respectively. Condensation with hydroxylamine, reduction
and acylation afforded amides 25 and 26. Finally, removal of the
Boc moiety and sulfonylation of the secondary amine led to puta-
tive, racemic GlyT1 inhibitor series 27 and 28.
As shown in Table 3, the homologated azetidine-based analogs
27 were uniformly more potent than the corresponding homolo-
gated piperidine-based analogs 28, affording GlyT1 inhibitors with
low nanomolar potency. While the 2,4-dichlorobenzamide was the
most potent congener, other benzamides displayed a wide range of
SFC, two as single species (GlyT1 IC50s > 10 lM), and one as a
mixture (GlyT1 IC50 = 34 2 nM); however, we were unable to
definitively assign the absolute stereochemistry. An enantioselec-
tive synthetic route (Scheme 2) was employed to quickly access
the pure cis-(3a,6a)-enantiomers 20a and 20b (Fig. 4).21 Following
the work of Beebe,21 azomethine ylide precursor 13 underwent a
dipolar cycloaddition reaction with cyclopentenone to give the
key racemic ketone 14, with cis-stereochemistry at the ring junc-
tion. Enantiomeric resolution via the (R)-tert-butyl sulfonamide
provided (3aS,6aR)-15 and (3aR,6aS)-15, which were subsequently
separated by silica gel chromatography, in accord with literature
precedent.21 Scheme 2 shows the complete route to 20a, employ-
ing (3aR,6aS)-15. Here, reduction with NaBH4 delivered 16,
followed by deprotection under acidic conditions to the primary
amine 17. Acylation, removal of the benzyl protecting group and
sulfonylation provided 20a, the (3aR,4R,6aS) isomer. By employing
(S)-tert-butyl sulfinamide, the other cis-(3a,6a)-enantiomers,
(3aR,4S,6aS) and (3aS,4R,6aR) could not be accessed.21 For the
isomers that could be obtained, enantiospecific inhibition was
noted with 20a, possessing a GlyT1 IC50 of 433 nM, while the other
GlyT1 potency (GlyT1 IC50s from 80 nM to 7 lM). Moreover, in the
azetidine series 27, the aryl/heteroaryl R1 moieties could be re-
placed with aliphatic groups and retain potency (R1 = iPr, GlyT1
IC50 = 394 nM; R1 = n-Pr, GlyT1 IC50 = 185 nM; R1 = cycPr, GlyT1
IC50 = 253 nM), whereas the corresponding analogs in the piperi-
dine series 28 were inactive.
Representative members from both 27 and 28 were evaluated
for their effect on enzyme kinetics of [14C]-glycine transport, and
both were shown to be competitive with glycine, as well as selec-
isomer 20b was inactive (GlyT1 IC50 > 10
lM). Interestingly, these
tive versus GlyT2 (IC50 > 30 lM). Initial evaluation in our in vitro
analogs were weak to inactive relative to racemic 12a, and sug-
gests that the active isomer(s) are either the trans-(3a,6a)-isomers
or the other cis congeners, and synthetic efforts to access both are
underway. Thus, 12b, derived from a scaffold-hopping exercise
employing 1–3, led to a novel [3.3.0]-based GlyT1 inhibitor with
in vitro properties comparable to other advanced GlyT1 inhibitors
in short order, and for which a U.S. patent was issued.22
In parallel, we were also preparing and evaluating other
piperidine bioisosteres and modifications to 1–3 to further access
additional novel intellectual property (IP) space. Modeling work
suggested that 4-position homologated piperidines, as well as
3-position homologated azetidines overlapped favorably with
DMPK assays demonstrated that 27c was stable in fortified rat liver
microsomes (75% parent remaining at 90 min), possessed a good
unbound fraction in rat (fu = 14%) and clean CYP profile (IC50-
s > 10 lM). An oral plasma:brain level (PBL) study with oral dosing
(10 mg/kg p.o. in 0.5% methocellulose) of 27c afforded a low
BrainAUC:PlasmaAUC of 0.11. SCF separation of the 27c enantiomers
led to the isolation of the two pure enantiomers, and one was quite
active (IC50 = 39 nM) while the other proved much weaker
(IC50 = 900 nM). In consultation with the Johnston group, they
developed an asymmetric synthesis of 27c, via chiral proton catal-
ysis of a secondary nitroalkane addition to an azomethine, and we
were able to elucidate that the potent enantiomer had the (S)-con-
figuration.23 Overall, the low brain:plasma ratios of these series,
11, 12, 27 and 28 diminished enthusiasm; however, the scaffold
hopping strategy again secured robust IP position for both the 27
and 28 series of GlyT1 inhibitors.24,25
In summary, we were able to successfully further scaffold hop
from 3, originally derived at from a scaffold hopping exercise from
1 and 2, and develop three new series for which US patents were
granted without the need for an HTS campaign. This was critical,
as the time required to perform a SPA-based HTS campaign and
identify/optimize the hits would have required far more time and
uncertain IP position in a highly crowded and competitive space.
These new series retained the potency and selectivity of the
advanced compounds from which they were derived, but did suffer
from only modest CNS exposure. Finally, all of these new series
displayed enantioselective inhibition of the GlyT1 transporter.
Further refinements are in progress and will be reported in due
course.
Table 3
Structures and activities of analogs 27 and 28
H
R1
N
R2
O
n
n
N
O
S
O
R3
27, n = 1
28
, n = 2
a
Compound
R1
R2
R3
GlyT1 IC50 (lM)
27a
28a
2,4-diClph
627
1500
N
27b
28b
2,4-diClPh
39
N
Acknowledgments
Me
201
This work was supported by the NIH/NIMH under a National
Cooperative Drug Discovery and Development grant U01
MH08795. D.J.S. is a recipient of a National Alliance for Research
on Schizophrenia and Depression (NARSAD)–Dylan Tauber Young
Investigator Award. Vanderbilt is a member of the MLPCN and
houses the Vanderbilt Specialized Chemistry Center for
Accelerated Probe Development supported by U54 MH084659.
The support of William K. Warren, Jr. who funded the William K.
Warren, Jr. Chair in Medicine (to C.W.L.) is gratefully
acknowledged.
N
N
27c
28c
2,4-diClPh
2,4-diClPh
68
46
N
Me
N
S
27d
28d
40
N
Me
374
a
IC50s represent single determinations performed in triplicate.

1066
D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1062–1066
17. Lindsley, C. W.; Zhao, Z.; Leister, W. H.; O’Brien, J. A.; Lemiare, W.; Williams, D.
References and notes
L., Jr.; Chen, T.-B.; Chang, R. S. L.; Burno, M.; Jacobson, M. A.; Sur, C.; Kinney, G.
G.; Pettibone, D. J.; Tiller, P. R.; Smith, S.; Tsou, N. N.; Duggan, M. E.; Conn, P. J.;
Hartma, G. D. ChemMedChem 2006, 1, 807.
1. Langdon, S. R.; Ertl, P.; Brown, N. Mol. Inf. 2010, 29, 366.
2. Sun, H.; Tawa, G.; Wallqvist, A. Drug Discov. Today 2012, 17, 310.
3. Martin, Y. C.; Muchmore, S. QSAR Comb. Sci. 2009, 28, 797.
4. Xiang, Z.; Thompson, A. D.; Brogan, J. T.; Schulte, M. L.; Mi, D.; Lewis, L. M.;
Yang, L.; Zhou, B.; Melancon, B. J.; Morrison, R.; Santomango, T.; Byers, F.;
Brewer, K.; Aldrich, J. S.; Yu, H.; Dawson, E. S.; Li, M.; McManus, O.; Jones, C. K.;
Daniels, J. S.; Conn, P. J.; Xie, X.; Weaver, C. D.; Lindsley, C. W. ACS Chem.
Neurosci. 2011, 2, 730.
5. Lindsley, C. W.; Shipe, W. D.; Wolkenberg, S. E.; Theberge, C. R.; Williams, D. L.,
Jr.; Sur, C.; Kinney, G. G. Curr. Top. Med. Chem. 2006, 8, 771.
6. Menniti, F. S.; Lindsley, C. W.; Conn, P. J.; Pandit, J.; Zagouras, P.; Volkmann, R.
A. Top. Med. Chem. 2013, 13, 26.
7. Olney, J. W.; Newcomer, J. W.; Farber, N. B. J. Psychiatry Res. 1999, 33, 523.
8. Coyle, J. T. Cell Mol. Neurobiol. 2006, 26, 365.
9. Kinney, G. G.; Sur, C. Curr. Neuropharmacol. 2005, 3, 35.
10. Bridges, T. M.; Williams, R.; Lindsley, C. W. Curr. Opin. Mol. Ther. 2008, 10, 591.
11. Lindsley, C. W.; Wolkenberg, S. E.; Kinney, G. G. Curr. Top. Med. Chem. 2006, 6,
1883.
18. Zhao, Z.; Leister, W. H.; O’Brien, J. A.; Lemiare, W.; Williams, D. L., Jr.; Jacobson,
M. A.; Sur, C.; Kinney, G. G.; Pettibone, D. J.; Tiller, P. R.; Smith, S.; Hartman, G.
D.; Lindsley, C. W.; Wolkenberg, S. E. Bioorg. Med. Chem. Lett. 2009, 19, 1488.
19. Wolkenberg, S. E.; Zhao, Z.; Wisnoski, D. D.; Leister, W. H.; O’Brien, J. A.;
Lemiare, W.; Williams, D. L., Jr.; Jacobson, M. A.; Sur, C.; Kinney, G. G.;
Pettibone, D. J.; Tiller, P. R.; Smith, S.; Gibson, C.; Ma, B. K.; Polsky-Fisher, S. L.;
Lindsley, C. W.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2009, 19, 1492.
20. Lowe, J. A. I. I. I.; Hou, X.; Schmidt, C.; Tingley, F. D. I. I. I.; McHardy, S.; Kalman,
M.; DeNinno, S.; Sanner, M.; Ward, K.; Lebel, L.; Tunucci, D.; Valnetine, J. Bioorg.
Med. Chem. Lett. 2009, 19, 2974.
21. Beebe, X.; Darczak, D.; Henry, R. F.; Vortherms, T.; Janis, R.; Namovic, M.;
Donnelly-Roberts, D.; Kage, K. L.; Surowy, C.; Milicic, I.; Niforatos, W.; Swensen,
A.; Marsh, K. C.; Wetter, J. M.; Franklin, P.; Baker, S.; Zhong, C.; Simler, G.;
Gomez, E.; Boyce-Rustay, J. M.; Zhu, C. Z.; Stewart, A. O.; Jarvis, M. F.; Scott, V. E.
Bioorg. Med. Chem. 2012, 20, 4128.
22. Lindsley, C.W.; Conn, P.J.; Williams, R.; Sheffler, D.J. US 8,211,933, 2012.
23. Davis, T. A.; Danneman, M. W.; Johnston, J. N. Chem. Commun. 2012, 5578.
24. Lindsley, C.W.; Conn, P.J.; Williams, R.; Jones, C.K.; Sheffler, D.J. US 8,207,155,
2012.
25. Lindsley, C.W.; Conn, P.J.; Williams, R.; Jones, C.K.; Sheffler, D.J. US 8,436,019,
2013.
12. Wolkenberg, S. E.; Sur, C. Curr. Top. Med. Chem. 2010, 10, 170.
13. Hashimoto, K. Curr. Pharm. Des. 2011, 17, 112.
14. For information on RG1678, please see: www.roche.com.
15. Jones, C.K.; Sheffler, D.J.; Williams, R.; Jadhav, S.B.; Felts, A.S.; Morrison, R.D.;
Niswender, C.M.; Daniels, J.S.; Conn, P.J.; Lindsley, C.W. Bioorg. Med. Chem. Lett.
2014, 24, 1067.
16. Manka, J. T.; Rodriguez, A. L.; Venable, D. F.; Morrison, R. D.; Venable, D. F.;
Plumley, H. C.; Blobaum, A. L.; Daniels, J. S.; Niswender, C. M.; Conn, P. J.;
Lindsley, C. W.; Emmitte, K. A. Bioorg. Med. Chem. Lett. 2013, 23, 5091.