Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties

Article abstract of DOI:10.1016/j.bmcl.2008.09.023

This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.

Full text of DOI:10.1016/j.bmcl.2008.09.023

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5439–5442
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I:
Exploration of alternative benzyl and privileged structure moieties
Thomas M. Bridges a,c, , Ashley E. Brady a,c, , J. Phillip Kennedy b, R. Nathan Daniels b, Nicole R. Miller a,
Kwango Kim c, Micah L. Breininger a, Patrick R. Gentry a, John T. Brogan b, Carrie K. Jones a,c
,
P. Jeffrey Conn a,c, Craig W. Lindsley a,b,c,
*
a Department of Pharmacology, Vanderbilt University Medical Center, 802 Robinson Research Building, Nashville, TN 37232, USA
b Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
c Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2008
Revised 3 September 2008
Accepted 5 September 2008
Available online 10 September 2008
This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue
library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural
changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Allosteric
Agonist
TBPB
Muscarinic receptor
The muscarinic acetylcholine receptors (mAChRs) are members
of the GPCR family A that mediate the metabotropic actions of the
neurotransmitter acetylcholine (ACh).1–3 To date, five distinct sub-
types of mAChRs (M1–M5) have been cloned and sequenced. M1,
M3 and M5 activate phospholipase C and calcium through Gq
whereas M2 and M4 block the action of adenylyl cyclase through
Gi/o.1–3 mAChR-regulated cholinergic signaling plays a critical role
in a wide variety of CNS and peripheral functions including mem-
ory and attention mechanisms, motor control, nociception, regula-
tion of sleep wake cycles, cardiovascular function, renal and
gastrointestinal function and many others.4–6 As a result, agents
that can selectively modulate the activity of specific mAChRs have
therapeutic potential in multiple pathological states.1–6 However,
due to high sequence conservation within the orthosteric binding
site of the five mAChR subtypes, historically it has been difficult
to develop subtype selective ligands.1–6 The native orthosteric
ligand for the mAChRs is acetylcholine 1 (ACh), and numerous
synthetic congeners such as carbachol 2 (CCh) have been employed
for assay development (Fig. 1).1–6 Prototypical mAChR activators
include the pan-mAChR agonists tascilidine 3 and oxotremorine
4 and the M1/M4 preferring agonist xanomeline 5.1–6 More re-
cently, AF267B 6 and related AF congeners have been reported as
M1 selective agonists.7 However, in our hands, AF267B 6 activates
M1, M3 and M5, and is M3 preferring.8 While AC-42 7 (an ectopic
O
O
O
N+
N+
O
H2N
O
N
Acetylcholine, 1
Carbachol, 2
Tascilidine, 3
O
S
O
N
N
S
HN
N
O
N
N
N
Oxotremorine, 4
Xanomeline, 5
AF267B, 6
N
O
H
H
MeO
MeO
H
N
H
N
O
H
O
AC-42, 7
brucine, 8
* Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343 6532.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
These authors contributed equally to this work.
Figure 1. Structures of representative orthosteric and allosteric mAChR activators.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.023

5440
T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5439–5442
agonist) and brucine 8 (an M1 positive allosteric modulator) lack
M1 potency and clean ancillary pharmacology to probe the effects
of selective M1 activation in vitro or in vivo, they validated that
allosteric sites can confer M1 mAChR-subtype selectivity by
exploiting allosteric binding sites.9,10
O
O
R1
R2
N
(a)
(b)
N
N
N
N
H
R1
HN
In numerous Phase II and III clinical trails, pan-mAChR agonists
were shown to improve cognitive performance in AD patients, nev-
ertheless, the GI- and/or cardiovascular side effects, resulting from
activation of peripheral mAChRs, were deemed intolerable and the
trials were discontinued.1–10 Importantly, both 3 and AF102B, a con-
gener of 6, promoted a reduction of Ab42 in the cerebral spinal fluid
of AD patients, suggestingthat mAChRactivationhas thepotentialto
be disease modifying as well as providing palliative cognitive ther-
apy.1–10 More recent studies in 3xTg-AD mice with 6 further support
a disease modifying role for mAChR activation.1–10 Interestingly, the
M1/M4 preferring 5, in addition to improving cognitive perfor-
mance, had robust therapeutic effects on the psychotic symptoms
and behavioral disturbances associated with AD, and more recently
demonstrated positive effects in a schizophrenia trial.11,12
O
10
11
12
Scheme 1. Reagents and conditions: (a) K2CO3, R1Br, DCM, 70–88%; (b) MP-
B(OAc)3H, 4-(2-keto-1-benzoimidazolinyl)piperidine or 5-chloro-1-(4-piperidinyl)-
2-benzimidazolone, DCM, rt, 24 h, 85–95%. All compounds purified by mass-
directed HPLC to analytical purity (>98%).15
Table 1
Functional activity of TBPB analogues 12
R1
R2
N
N
N
We recently reported on TBPB 9, a potent, centrally active and
highly selective M1 allosteric agonist, which displayed robust effi-
cacy in several preclinical antipsychotic models as well as signifi-
cant effects on the processing of amyloid precursor protein (APP)
towards the non-amyloidogenic pathway and decreased Ab pro-
duction.8 However, TBPB 9 was an un-optimized screening lead
HN
12
O
a
a
Compound
R1
R2
M1 EC50 (nM)
%CCh Maxa
D2 IC50
(lM)
TBPB
12a
12b
12c
12d
12e
12f
12g
12h
12i
2-MeBn
CO2Et
2-MeBn
Bn
2-CF3Bn
2-CF3Bn
2-CIBn
2-CIBn
2-NO2Bn
2-NO2Bn
2-CNBn
2-CNBn
H
H
289
2.1
1030
356
410
1500
260
1800
120
1100
490
1600
82
65
84
74
82
83
44
49
48
42
23
27
2.65
>10
with antagonist activity at D2 (IC50 = 2.6
l
M).8,13 Despite an
18F]-fallypride micro-PET study that confirmed the antipsychotic
Cl
Cl
H
Cl
H
Cl
H
Cl
H
35% at 10
35% at 10
30% at 10
ND
l
l
l
M
M
M
[
activity observed with 9 was the result of selective M1 activation
and not due to inhibition of D2, we hoped to diminish D2 activity
through a lead optimization campaign.8 In this Letter, we describe
the synthesis, SAR and pharmacological profile of the first ana-
logues ever reported for this important M1 selective small mole-
cule probe (Fig. 2).
2.06
ND
1.13
ND
12j
12k
40% at 10
ND
lM
Lead optimization efforts employed an iterative parallel synthe-
sis approach as shown in Scheme 1.14 Analogues 12 were prepared
by a reductive amination sequence employing a functionalized
piperidone 11 and 4-(2-keto-1-benzoimidazolinyl)piperidine or
the 5-chloro congener and polymer-supported triacetoxy borohy-
dride.16 In the first round of library synthesis, efforts first focused
on commercially available piperidinones 11 (wherein R1 is either
an alkyl or carbamate moiety) to determine the effect of modulat-
ing basicity and/or topology. Subsequent rounds of library synthe-
sis utilized benzylic analogues of 11 generated by standard
alkylation chemistry with 10 and substituted benzyl halides. Table
1 highlights representative SAR for this effort. Out of the initial 24-
member library with simple aliphatic and carbamate derivatives of
11, only one retained M1 agonist activity. Compound 12a, an ethyl
carbamate analogue (Fig. 3) displayed improved M1 efficacy
(EC50 = 2.1 nM, 65% CCh Max), but lost selectivity versus M2–M5
Cl
a
EC50s, % CCh maximum and IC50s are the mean of at least three independent
determinations. All analogues in this table are selective for M1 (>50
l
M vs M2–M5),
except 12a. ND, not determined.
110
100
M1
M2
M3
M4
M5
90
80
70
60
50
40
30
20
10
0
100
M1
-12
-11
-10
-9
-8
-7
-6
M2
M3
M4
M5
80
60
40
20
0
Log [12a] (M)
N
O
Figure 3. Concentration response curves for TBPB analogue 12a at M1–M5. Data
represent mean + SEM of three independent determinations. M1 EC50 = 2.1 nM
(82.6% CCh Max), M2 EC50 = 11.9 nM (80.6% CCh Max), M3 EC50 = 113 nM (24.1%
CCh Max), M4 EC50 = 9.1 nM (96.9% CCh Max), M5 EC50 = 34.3 nM (50.8% CCh Max).
N
N
N
H
-11 -10
-9
-8
-7
-6
-5
-4
(EC50s = 11.9 nM, 113 nM, 9.1 nM and 34.3 nM, respectively)
degenerating into a pan-mAChR partial agonist.
TBPB, 9
Log [TBPB] (M)
In the second round of analogue synthesis, we focused on alter-
native benzyl moieties for the distal piperidine ring of TBPB while
maintaining the 4-(2-keto-1-benzoimidazolinyl)piperidine moiety,
Figure 2. Concentration response curves for TBPB (9) at M1–M5. Data represent
mean + SEM of three independent determinations. M1 EC50 = 289 nM, 82% CCh Max,
M2–M5 EC50 > 50 lM.

T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5439–5442
5441
a well known GPCR privileged structure, with either hydrogen or a
O
N
chlorine atom in the 5-position, the latter of which to block a site of
oxidative metabolism we identified. This effort generated over 60
analogues, and the SAR proved to be rather ‘flat’. If the benzyl
group possessed substituents in the 3- or 4-positions, all M1 agon-
N
R
(a)
N
R
ism was lost (EC50 > 20
synthesize other analogues with selective M1 partial agonism (M1
EC50s 120 nM to 1.8 M, >50 M vs M2–M5), but the degree of
lM). As shown in Table 1, it was possible to
N
F
l
l
N
H
O
agonism varied widely (23–84%). Incorporation of a 5-Cl atom into
TBPB to block metabolism results in 12b, a compound that main-
tains the same degree of agonism as TBPB, but loses ꢀ5-fold in effi-
cacy. Removal of the 2-Me group results in an analogue
comparable to TBPB (12c). Attempts to replace the metabolically
labile 2-methyl group with alternative chemical moieties (12d–
12k) generally led to a significant diminution in M1 agonism
(<50%), M1 efficacy, or both. However, the 2-nitrobenzyl analogue
12h proved more potent than TBPB (M1 EC50 = 120 nM), but the
degree of agonism fell to 42% of the maximum CCh response.
One exception to this was the 2-CF3 group, which provided an ana-
logue with an M1 EC50 of 410 nM and 82% of the maximum CCh
response.
18, R = CH3
19, R = CF3
20
Scheme 3. Reagents and conditions: (a) MP-B(OAc)3H, 4-, 5- and 6-fluoro-1-
(piperdin-4-yl)-1-H-benzo[d]imidazol-2(3H)-ones 17, 50–90%. All compounds puri-
fied were by mass-directed HPLC to analytical purity (>98%).15
Table 2
Functional activity of TBPB analogues 20
N
R
N
With respect to D2 inhibition, 12d maintained an mAChR pro-
file comparable to TBPB, but D2 inhibition was greatly diminished
F
N
(ꢀ30% at 10
lM), indicating that 12d might prove to be a more
useful small molecule tool to probe M1 than TBPB. The only ana-
HN
O
20
logue more potent than TBPB, 12h, also displayed increased D2
inhibition (IC50 = 1.13 lM); however, a dual M1 allosteric ago-
nist/D2 antagonist may prove to be an excellent profile for a novel
schizophrenia treatment.
We then decided to evaluate the effect of a small structural
modification and targeted fluorine-substituted 4-(2-keto-1-benzo-
imidazolinyl)piperidines, prepared by modification of the Merck
route (Scheme 2).17
a
a
Compound
R
F
M1 EC50
(lM)
%CCh Maxa
D2 IC50
>10
(lM)
20a
20b
20c
20d
20e
20f
CH3
CH3
CH3
CF3
CF3
CF3
4-F
5-F
6-F
4-F
5-F
6-F
1.06
0.85
0.76
1.71
1.04
>10
73
85
84
75
80
ND
40% at 10
>10
lM
>10
2.69
>10
Beginning with commercial fluorine-substituted ortho-fluoro-
nitroaromatic compounds 13 were heated under microwave irradi-
ation with ethyl 4-amino-1-piperdinecarboxylate to deliver the
SNAr products 14 in yields ranging from 70% to 90%. A zinc medi-
ated nitro reduction afforded 15 which was then treated with tri-
phosgene to provide the benzimidazolone 16. Removal of the
ethyl carbamate was accomplished under another microwave-
a
EC50s, % CCh maximum and IC50s are the mean of at least three independent
determinations. All analogues in this Table are selective for M1 (>50
M5). ND, not determined.
lM vs M2–
assisted protocol to deliver the 4-, 5- and 6-fluoro-1-(piperdin-4-
yl)-1-H-benzo[d]imidazol-2(3H)-ones 17 in 50–60% yield from 14
(Scheme 2).
Analogues 20 were prepared by a reductive amination sequence
employing either 2-methyl benzyl piperidone 18 or 2-trifluoro-
methyl benzyl piperidone 19 and the 4-, 5- or 6-fluoro-1-(piper-
din-4-yl)-1-H-benzo[d]imidazol-2(3H)-ones 17 (Scheme 3). As
shown in Table 2, TBPB analogues 20 containing a fluorine atom
were uniformly less active than the unsubstituted parents, TBPB
and 12d. However, analogues such as 20b and 20c possessed sub-
micromolar EC50s and were fully efficacious (850 nM, 85% CCh
max and 760 nM, 84% CCh max, respectively); moreover, they affor-
ded no significant D2 inhibition. Based on these data, we prepared
additional 4-(2-keto-1-benzoimidazolinyl)piperidines and TBPB
analogues with alternative substitutions (Br, CN, CF3), but most were
found to be either inactive, or partial agonists with <20% efficacy, or
they were no longer selective for M1. After hundreds of analogues
had been synthesized and evaluated, we found that this was a rare
instance, from our experience, where the original screening lead,
TBPB, could not be significantly improved upon. However, we have
encountered ‘flat’ SAR with other allosteric ligands for class C GPCRs
such as mGluR5.18–20
CO2Et
N
CO2Et
N
F
(a)
(b)
NO2
NH
NH
F
F
F
NO2
NH2
13
14
15
CO2Et
N
H
N
(c)
(d)
N
N
O
F
O
F
N
H
N
H
In summary, we have identified a novel series of allosteric
partial to full agonists with high selectivity for M1 versus M2–
6
1
17
M5 based on
a
(1-(10-substituted)-1,40-bipiperidin-4-yl)-1H-
Scheme 2. Reagents and conditions: (a) ethyl 4-aminopiperidine, Na2CO3, KI,
cyclohexanol, w, 180 °C, 10 min, 70–90%; (b) Zn, 1 N HCl, MeOH; (c) triphosgene,
Et3N, THF, rt, 2 h; (d) 10% NaOH, w, 130 °C, 30 min, 50–60% from 14. All
compounds purified were by mass-directed HPLC to analytical purity (>98%).15
benzo[d]imidazol-2(3H)-one scaffold. SAR was ‘flat’ within the
TBPB series, with subtle changes resulting in pan-mAChR agonism,
loss of M1 efficacy, significant decreases in the degree of partial
l
l

5442
T. M. Bridges et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5439–5442
loaded with MP-B(OAc)3H (142 mg, 0.345 mmol, 2.42 mmol/g, 3.0 equivalents)
and 4-(2-keto-1-benzoimidazolinyl)piperidine (25 mg, 0.115 mmol,
agonism or undesirable ancillary pharmacology. For instance, 12h
afforded an over 2-fold improvement in M1 EC50, relative to TBPB,
but the degree of agonism diminished to 48% of CCh max. This was
a rare example in which the screening lead TBPB could not be opti-
mized, but possessed a profile that enabled both in vitro and
in vivo studies to be conducted. Moreover, this study further exem-
plifies the challenges in the development of allosteric ligands for
GPCRs. Further refinements to the TBPB scaffold are in progress
and will be reported in due course.
1.0 equivalents) or 5-chloro-1-(4-piperidinyl)-2-benzimidazolone (29 mg,
0.115 mmol, 1.0 equivalents). Then, one of 64 tertiary amine hydrates
(0.115 mmol, 1.0 equivalents) from the previous alkylation reactions was
added to each vial, and the reactions were stirred overnight at room
temperature. The next day, the solutions were filtered and washed with CH2Cl2
(3ꢁ 3 mL), then dried before purification by mass-directed preparative HPLC.
TBPB, 1-(10-2-methylbenzyl)-1,40-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-
one (9). To
a stirred solution of 4-piperidone monohydrate HCl (2.00 g,
13.02 mmol) in dimethylformamide (100 mL) was added 2-methylbenzyl
bromide (2.44 g, 13.02 mmol) and K2CO3 (3.60 g, 26.04 mmol, 2.0 equivalents)
at room temperature. The reaction was then monitored by analytical LC–MS, and
once judged complete; the reaction was separated with water and EtOAc. The
organics were next washed with a saturated solution of NaCl and dried over
MgSO4 before being concentrated in vacuo to afford 2.59 grams (90%) of the
Acknowledgments
The authors thank the NIH and NIMH for support of our pro-
grams (1RO1MH082867-01). The authors specifically acknowledge
the support of a Vanderbilt Institute of Chemical Biology Pilot Pro-
ject Grant, the Alzheimer’s Association (IIRG-07-57131). T.M.B.
acknowledges an ITTD (T90-DA022873) pre-doctoral training grant
and A.E.B. is supported by a National Research Service Award
(1FM32 MH079678-01).
hydrate form of the piperidone 1-(2-methylbenzyl)piperidin-4,4-diol as
a
colorless oil. Analytical LC–MS (J-Sphere80-C18, 3.0 ꢁ 50.0 mm, 4.1 min
gradient, 5% [0.05% TFA/CH3CN]:95% [0.05% TFA/H2O]:1.64 min, >99% (214 nm,
254 nm and ELSD) M+1 peak m/e 204.1; 1H NMR (400 MHz, DMSO-d6) d7.28 (m,
1H), 7.16 (m, 3H), 3.53 (s, 2H), 2.67 (t, J = 6.4 Hz, 4H), 2.36 (s, 3H), 2.32 (t,
J = 6.4 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) d 137.0, 136.4, 130.1, 129.3, 127.0,
125.4, 58.7, 52.4, 40.6, 18.8; HRMS calcd for C13H20NO2[M+H]; 222.1494 found
222.1488. 1-(2-Methylbenzyl)piperidin-4,4-diol (2.00 g, 9.04 mmol) was then
brought up in a stirred solution of CH2Cl2 (100 mL) to which 4-(2-keto-1-
benzimidazolinyl)piperidine (2.16 g, 9.95 mmol, 1.1 equivalents) was added at
room temperature. Then, MP-triacetoxyborohydride (13.57 g, 27.132 mmol
[2.0 mmol/g loading], 3.0 quivalents) was added and the reaction was
monitored by analytical LC–MS. Once judged complete, the reaction was
filtered and the filtrate was purified by mass-directed preparative HPLC to
afford 2.92 g (80%) of title compound as a pure white solid. Analytical LC–MS
(J-Sphere80-C18, 3.0 ꢁ 50.0 mm, 4.1 min gradient, 5% [0.05% TFA/
CH3CN]:95%[0.05% TFA/H2O]:2.34 min, >99% (214 nm, 254 nm and ELSD) M+1
peak m/e 405.2; 1H NMR (400 MHz, DMSO-d6) d 10.94 (s, 1H), 9.97 (br s, 1H), 7.31
(d. J = 4.4 Hz, 1H), 7.00 (m, 3H), 4.57 (m, 1H), 4.12 (br d, J = 11.6 Hz, 2H), 4.04 (q,
J = 7.2 Hz, 2H), 3.59 (br d, J = 11.2 Hz, 2H), 3.47 (m, 1H), 3.24 (m, 2H), 2.82 (m, 2H),
2.66 (m, 2H), 2.05 (m, 2H), 1.94 (br d, J = 12.4 Hz, 2H), 1.59 (m, 2H), 1.19 (t,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) d 154.4, 153.6, 128.7, 128.4, 120.9,
120.3, 109.1, 108.6, 62.5, 60.9, 48.1, 46.6, 42.1, 25.8, 14.5; HRMS calcd for
C25H33N4O[M+H]; 405.2654 found 405.2654; Ethyl 4-(2-oxo-2,3-dihydro-1H-
References and notes
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benzo[d]imidazol-1-yl)-1,40-bipiperidine-10-carboxylate (12a). To
a
stirred
solution of 4-(2-keto-1-benzimidazolinyl)piperidine (50 mg, 0.230 mmol) in
CHCl2 (3 mL) was added ethyl 4-oxo-1-piperidinecarboxylate (43.3 mg,
0.253 mmol, 1.1 equivalents) and MP-B(OAc)3H (285 mg, 0.691 mmol,
2.42 mmol/g, 3.0 equivalents). The reaction was then monitored by analytical
LC–MS, and once judged complete; the reaction was filtered and concentrated.
Purification by mass-directed preparative HPLC afforded 32.50 mg (38%) of title
compound as
a beige-white solid. Analytical LC/MS (J-Sphere80-C18,
3.0 ꢁ 50.0 mm, 4.1 min gradient, 5% [0.05% TFA/CH3CN]:95% [0.05% TFA/H2O]:
2.05 min, >99% (214 nm, 254 nm and ELSD) M+1 peak m/e 373.2; 1H NMR
(400 MHz, DMSO-d6) d10.94 (s, 1H), 9.97 (br s, 1H), 7.31 (d, J = 4.4 Hz, 1H), 7.00
(m, 3H), 4.57 (m, 1H), 4.12 (br d, J = 11.6 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.59 (br d,
J = 11.2 Hz, 2H), 3.47 (m, 1H), 3.24 (m, 2H), 2.82 (m, 2H), 2.66 (m, 2H), 2.05 (m,
2H), 1.94 (br d, J = 12.4 Hz, 2H), 1.59 (m, 2H), 1.19 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6) d 154.4, 153.6, 128.7, 128.4, 120.9, 120.3, 109.1, 108.6, 62.5,
60.9, 48.1, 46.6, 42.1, 25.8, 14.5; HRMS calcd for C20H29N4O3[M+H]; 373.2240
found 373.2235.
17. Burgey, C. S.; Stump, C. A.; Nguyen, D. M.; Deng, J. Z.; Quigley, A. G.; Norton, B.
R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan,
K. S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Bioorg. Med. Chem. Lett. 2006, 16,
5052.
18. O’Brien, J. A.; Lemaire, W.; Chen, T-B.; Chang, R. S. L.; Jacobson, M. A.; Ha, S. N.;
Lindsley, C. W.; Sur, C.; Pettibone, D. J.; Conn, J.; Wiliams, D. L. Mol. Pharmacol
2003, 64, 731.
19. Zhao, Z.; Wisnoski, D. D.; O’Brien, J. A.; Lemiare, W.; Williams, D. L., Jr.;
Jacobson, M. A.; Wittman, M.; Ha, S.; Schaffhauser, H.; Sur, C.; Pettibone, D. J.;
Duggan, M. E.; Conn, P. J.; Hartman, G. D.; Lindsley, C. W. Bioorg. Med. Chem.
Lett. 2007, 17, 1386.
20. Sharma, S.; Rodriguez, A.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett.
2008, 18, 4098.
16. Experimental details: Synthesis of N-benzyl piperidinones. Each of 64 glass
reaction vials containing 3 mL of CH2 Cl2 and 0.1 mL of MeOH were loaded with
piperidone hydrochloride (25 mg, 0.185 mmol, 1.0 equivalents) and K2 CO3
(51 mg, 0.370 mmol, 2.0 equivalents). Then, one of 64 functionalized benzyl
bromides (0.185 mmol, 1.0 equivalents) was added to each reaction tube. The
reactions were stirred overnight at room temperature, partitioned between
CH2Cl2 and H2O, and the organics were concentrated on a heat–air block.
Purification by preparative LC–MS was performed to afford N-benzyl
piperidinones products for subsequent reductive amination. Reductive
amination. Each of 64 glass reaction vials containing 3 mL of CH2Cl2 were