Evaluation of 4′-substituted bicyclic pyridones as non-steroidal inhibitors of steroid 5α-reductase

Article abstract of DOI:10.1016/j.bmcl.2007.04.049

4′-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5α-reductase (SR). A range of 4′-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different cla

Full text of DOI:10.1016/j.bmcl.2007.04.049

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3603–3607
Evaluation of 40-substituted bicyclic pyridones as
non-steroidal inhibitors of steroid 5a-reductase
Anna R. McCarthy,a,* Rolf W. Hartmannb and Andrew D. Abella
aDepartment of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8020, New Zealand
bPharmaceutical & Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbru¨cken, Germany
Received 20 February 2007; revised 17 April 2007; accepted 18 April 2007
Available online 24 April 2007
Abstract—40-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5a-
reductase (SR). A range of 40-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different
classes of non-steroidal inhibitors of SR. Bicyclic pyridones containing a 40-benzoyl or long carbon chain tether showed more potent
inhibition against type 1 SR than inhibitors with N-substituted acetamide groups in the 40-position. SAR derived from 40-substituted
bicyclic pyridones reported here do not correlate with SAR derived from known potent 40-substituted biaryl acid SR inhibitors. A
40-benzoyl group is favoured by the active site in both isozymes.
Ó 2007 Elsevier Ltd. All rights reserved.
Steroid 5a-reductase is an NADPH-dependent enzyme
that catalyses the irreversible bioreduction of testoster-
one to the more potent androgen dihydrotestosterone
(DHT). Two isozymes of SR exist, type 1 and type 2,
whose tissue distribution and kinetics differs.1 Major
target tissues of DHT include the prostate, skin, scalp
and sebaceous gland (see Occhiato et al. and references
therein).2 Elevated levels of DHT are associated with
prostate disorders (cancer and benign prostatic hyper-
plasia)2 and skin disorders such as androgenetic alopecia
(male pattern baldness), acne and hirsutism.3 Due to the
association of DHT with these disorders, there is signif-
icant interest in developing SR inhibitors as potential
therapeutics. Modification of the natural substrate led
to the generation of steroidal inhibitors such as 14 and
2,5 but recent work has focussed on developing non-ste-
roidal inhibitors with tricyclic or bicyclic scaffolds that
mimic the steroid backbone (e.g., 3,6 4,7 5a/5b8,9 and
610). Non-steroidal inhibitors are currently of significant
interest as they potentially avoid the well-known side
effects associated with steroidal drugs.
Structural diversity is found amongst the different clas-
ses of non-steroidal compounds known to inhibit SR.
However, a structural feature common to these inhibi-
tors is a lipophilic scaffold incorporating a ring which
mimics the geometry and electrostatic properties of the
A ring of the proposed enolate intermediate in the bio-
reduction.2 The potency and selectivity of non-steroidal
inhibitors depends greatly on the nature and position
of ring substituents. The number of different classes of
non-steroidal SR inhibitors has made the definition of
structure–activity relationships (SAR) within and across
these classes necessary. In this paper, we report SAR
derived from novel compounds with non-steroidal bicy-
clic scaffolds, 5- and 1-aryl substituted pyridones (e.g., 6
and 7). As substituents at the 40-position are known to
influence the potency of known bicyclic SR inhibitors,
particular substituents were chosen for incorporation
at the 40-position of the bicyclic pyridone scaffolds to
examine SAR for this position. Potent inhibitors con-
taining N-substituted acetamide or benzoyl substituents
at the 40-position are found within a class of non-steroi-
dal inhibitors consisting of a biaryl acid scaffold (e.g., 5a
and 5b). These and related moieties were incorporated
into the 40-position of the bicyclic pyridones reported
here. The biaryl acids 5a and 5b represent non-steroidal
derivatives of the steroidal acid 2, with two of the steroi-
dal rings (B and D) missing. They are also related to the
non-steroidal tricyclic aryl acid compound 4 in which
the steroidal D ring is absent. The same relationships
Keywords: Pyridone; Non-steroidal; Steroid 5a-reductase; Structure–
activity relationships.
*
Corresponding author at present address: School of Chemistry,
Biomolecular Sciences Building, University of St. Andrews, North
Haugh, St. Andrews KY16 9ST, Scotland, UK. Tel.: + 44 1334
467242; fax: + 44 1334 462595; e-mail: am160@st-andrews.ac.uk
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.049

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A. R. McCarthy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3603–3607
can also be observed for the aza-type compounds 1, 3
and 5. To examine SAR for the 40-position, a series of
40-substituted 5-arylpyridones (13–15, 17, 26 and 27)
were prepared, along with some corresponding 1-aryl-
pyridone derivatives (20 and 21), and tested against
SR types 1 and 2 expressed in transfected human embry-
onic kidney cells. SR inhibitors consisting of a substi-
tuted 1-arylpyridone scaffold of the type depicted by 7
have not been reported to date and thus present a novel
non-steroidal bicyclic scaffold with which to investigate
SR inhibition. Compounds 26 and 27 contain a long car-
bon chain tether which was incorporated to facilitate
their potential attachment to a gold surface. Solid sup-
ported biologically active compounds provide well-de-
to give the phenol 10. Alkylation of 10 with bromoace-
tamide 1111 or 12 gave target compounds 13 and 14,
respectively. Piperidone 15 was prepared by catalytic
hydrogenation of 13. The synthetic route to pyridone
17 was slightly modified, whereby 8 was converted to
6-fluoropyridin-3-yl boronic acid12 to facilitate Suzuki
cross coupling with benzyl-4-bromophenyl ketone to
give the key bicyclic intermediate 16. Acid hydrolysis
of 16 and subsequent N-methylation gave target com-
pound 17.
1-Aryl 2-methyl 2,3-dihydro-4-pyridones 20 and 21
(Scheme 2) were prepared from racemic key intermedi-
ate 18 which was synthesised via aza Diels-Alder
methodology using Danishefsky’s diene, acetaldehyde
and p-anisidine.13 Deprotection of the aryl methyl ether
of 18 gave phenol 19 which was alkylated with bromoac-
etamide 11 or 12 to give target compounds 20 and 21,
respectively.
fined
systems
for
investigating
biomolecular
recognition, such as that between an enzyme and inhib-
itor. SAR obtained for the compounds reported were
compared to SAR derived from inhibitors within the
bicyclic pyridone class as well as inhibitors from the bia-
ryl acid class, providing further information about the
structural features common to different classes of non-
steroidal SR inhibitors (Fig. 1).
Long carbon chain tethers containing a terminal olefin
(24 and 25) were prepared for subsequent attachment
to proposed inhibitor 14 using cross metathesis. Com-
pounds 22 and 23 were prepared according to Svedham
et al.14 and coupled to 4-pentenoic acid in the presence
of DMAP and EDCI to give tethers 24 and 25. The
inhibitor-tether conjugates 26 and 27 were prepared by
reacting proposed inhibitor 14 with tether 24 or 25 in
the presence of Grubbs’ second generation catalyst (only
the E isomers were obtained). These long carbon chain
tethers were incorporated into compound 14 to facilitate
its potential attachment to a gold surface (Scheme 3).
Synthesis. 5-Aryl 1-methyl-2-pyridones 13–15 were pre-
pared from the key bicyclic intermediate 9 (Scheme 1),
which was synthesised via Suzuki cross coupling of the
commercially available pyridine 8 and p-methoxyphenyl
boronic acid. Acid hydrolysis of 9 was followed by N-
methylation and deprotection of the aryl methyl ether
Inhibition of SR type 1 and 2. The inhibitory activity
(% inhibition at 10 lM) of compounds reported here
(Table 1) against SR type 1 and 2 was evaluated against
Assay procedure: SR type 1 and 2 transfected HEK293 cells were
washed with PBS buffer and harvested in cold homogenate buffer
(Tris–HCl, EDTA and sucrose). Cells were homogenised on ice. Test
compound solutions (10 lM in DMSO) were incubated with cell
homogenate (total volume 500 lL using Tris–HCl buffer, EDTA).
This high test compound concentration was used as inhibitory
activity could not be detected at lower concentrations. The incubation
mixture included NADP+, glucose-6-phosphate, glucose-6-phosphate
dehydrogenase, androstenedione (AD) (500 nM with 3.2 lCi [1b-3H]-
AD) and 2% MeOH. Androstenedione was used as the substrate as it
has a higher affinity for SR type 1 compared to testosterone
(androstenedione and testosterone have similar affinities for SR type
2). The Km values for androstenedione in the cell-free homogenate are
852 nM (type 1) and 57 nM (type 2). Km values for testosterone are 1–
5 lM (type 1) and 4–50 nM (type 2).2 Addition of the enzyme
preparation to the test compound solution started the reaction, which
was stopped by extracting the steroids with cold diethyl ether.
Collection of the ether layer after centrifugation gave the steroids
which were dissolved in 50 lL MeOH for HPLC analysis. HPLC
analysis was carried out with Agilent 1100 series, Agilent Chemsta-
tion for LC 3D. The dissolved steroids (AD and androstanedione,
12.5 lL) were injected. Radioactivity was measured with a Berthold
radioflow monitor LB509. Methanol/water (65:35) was used as the
mobile phase with a flow of 0.35 mL minꢀ1, and additive flow of
1 mL for scintillator (quickszint flow 302) and RP 18 Nucleodur
column. Baseline separation of steroidal substrates and products was
achieved within 15 min. Results are expressed as the amount of
androstanedione formed as a percentage of control values.
Figure 1. Some known steroidal inhibitors (1 and 2) of SR and related
non-steroidal tricyclic (3 and 4) and bicyclic inhibitors (5 and 6).
Structure 7 represents a novel scaffold for the inhibition of SR as
reported here.

A. R. McCarthy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3603–3607
3605
Scheme 1. Reagents and conditions: (i) p-methoxyphenyl boronic acid, Pd(PPh3)4, KOH, n-Bu4NBr, THF, reflux, 19 h (82%); (ii) 4 M HCl in
dioxane, H2O, reflux, 24 h (quant.); (iii) LiH, DMF, 50 °C, 1.5 h then MeI, 16 h (68%); (iv) HBr in AcOH, reflux, 16 h (83%); (v) 2 M aq KOH,
DMF, 80 °C, 1.5 h, then 11 or 12, 16 h [13 (46%), 14 (79%)]; (vi) H2, Pd/C, 40 bar, EtOH, rt (63%); (vii)12; (viii) benzyl-4-bromophenyl ketone,
Pd(PPh3)4, 2 M aq Na2CO3, EtOH, PhMe, reflux, 18 h (85%); (ix) as for step (ii); (x) LiH, DMF, rt, 1 h, then MeI, 16 h (52%).
Scheme 2. Reagents and conditions: (i) HBr in AcOH, 80 °C, 8 h (66%); (ii) 2 M aq KOH, DMF, 80 °C, 1 h, then 11 or 12, 16 h [20 (43%), 21 (30%)].
Scheme 3. Reagents and conditions: (i) DMAP, 4-pentenoic acid, EDCI, CH2Cl2, rt, 3 h [22 (49%), 23 (62%)]; (ii) 20 mol% Grubbs’ 2nd generation
catalyst, 1,1,2-trichloroethane, rt, 16 h [26 (30%), 27 (52%)].
isozymes expressed separately by transfected human
embryonic kidney (HEK) cells.15 HEK-I (expressing
type 1 SR) and HEK-II (type 2 SR) cell-free homoge-
nates were used. Weak inhibition against the type 1
isozyme was observed for compounds with 40-N-substi-
tuted acetamide compounds 13–15, 20 and 21. More
potent inhibition of type 1 SR was observed for com-
pounds 26 and 27 which have long carbon chain tethers
attached to the 40-acetamide, and also 17 which has a
40-benzoyl substituent. This finding provides further evi-
dence that large hydrophobic groups are tolerated in a
region of the active site not involved in the enzymatic
reaction. Similar inhibitory activities against type 1 SR
are observed for compounds with an N-methylated lac-
tam ring (13 and 14) compared to those with a 2-methyl
2,3-dihydro-4-pyridone ring (20 and 21) (cf 13/20, and
14/21). A benzoyl group clearly enhances the potency
of 17 when compared to inhibitors containing N-substi-
tuted acetamide groups (13, 14, 20 and 21). This obser-
vation correlates with that reported by Hartmann et al.
who noted that the presence of bulky ketones at the
40-position of 5-aryl pyridones enhanced inhibitory
potency compared to compounds with amides at the
40-position.16 Inhibition against the type 2 isozyme was
only observed for compound 21 which also inhibited
type 1 SR very weakly.

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A. R. McCarthy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3603–3607
SAR for 40-substituents derived from the biaryl carbox-
Table 1. Inhibition of type 1 and 2 SR
Type 1a (% inhibition Type 2b (% inhibition
ylic acid inhibitors. In addition, a novel type of non-ste-
roidal scaffold for inhibiting SR has been reported,
which may allow further development of more potent
non-steroidal inhibitors of SR. The bicyclic pyridones
reported here are related to the tricyclic benzo[f]quinoli-
none 3, all of which are non-steroidal mimics of the
aza-steroid inhibitor 1. The biaryl acid SR inhibitors
discussed (e.g., 5a/5b) are related to the tricyclic aryl
acid 3 and are non-steroidal mimics of steroidal inhibi-
tor 2. The inhibitory activities reported here provide
further evidence that the nature of the substituent at
the 40-position of non-steroidal bicyclic inhibitors has
a profound effect on potency and selectivity against
SR types 1 and 2.
Compound
at 10 lM)
at 10 lM)
13
14
15
17
20
21
26
27
8
—
—
—
6
6
61
3
—
12
—
—
25c
8
43
33
Finasteride (9f) 453c
a HEK-I cell homogenate.
b HEK-II cell homogenate.
c IC50 (nM).
N,N-Diisopropyl-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-
3-yl)phenoxy)acetamide (13). 1H NMR (CD3OD,
500 MHz) d 1.24 (d, 6H, J = 6.4 Hz, (CH3)2), 1.39 (d,
6H, J = 6.4 Hz, (CH3)2), 3.43 (m, 1H, CH(CH3)2), 3.61
(s, 3H, NCH3), 4.09 (m, 1H, CH(CH3)2), 4.72 (s, 2H,
CH2), 6.59 (d, 1H, J = 9.3 Hz, COCH@CH), 7.00 (d,
2H, J = 8.8 Hz, ArH), 7.43 (d, 2H, J = 8.8 Hz, ArH),
7.80 (dd, 1H, J = 2.4, 9.3 Hz, COCH@CH), 7.86 (d, 1H,
J = 2.4 Hz, NCH3CH). HRMS (M+H). Found:
343.2032 (Calcd for C20H27N2O3: 343.2022).
The substituent present at the 40-position of non-steroi-
dal bicyclic inhibitors is influential on both type 1 and 2
SR inhibition potencies. Potent biaryl acid compound
5a (IC50 = 9.8 nM)8 contains an OCH2 linker between
the aromatic ring and N-diisopropylamide group at
the 40-position. This linker was incorporated into the
40-position of the 5-aryl 1-methyl-pyridone scaffold
reported here to give novel compounds 13 and 15 with
40-N-substituted acetamides. However the presence of
the OCH2 linker in 13 and 15 did not result in potent
inhibitory activity for these compounds (6% and 8%
inhibition of type 1 activity, respectively). This is a sig-
nificant result for defining SAR across different classes
of SR inhibitors. For the pyridone inhibitors, SAR for
40-substituents do not correlate with SAR derived from
the biaryl acid class.
N-Allyl-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phen-
1
oxy)acetamide (14). H NMR (CD3OD, 500 MHz) d
3.65 (s, 3H, NCH3), 3.89 (d(br), 2H, J = 5.4 Hz,
NHCH2), 4.55 (s, 2H, OCH2), 5.13 (m, 2H, CH@CH2),
5.85 (m, 1H, CH@CH2), 6.62 (d, 1H, J = 9.3 Hz,
COCH@CH), 7.06 (d, 2H, J = 8.8 Hz, ArH), 7.48 (d,
2H, J = 8.8 Hz, ArH), 7.83 (dd, 1H, J = 2.4, 9.3 Hz,
COCH@CH), 7.90 (d, 1H, J = 2.4 Hz, NCH3CH).
HRMS (M+H). Found: 299.1390 (Calcd for
C17H19N2O3: 299.1396).
Inhibitor 17 was based on known potent compound 5b
(Ki = 60 nM for type 2 SR)9 which possesses a benzoyl
group at the 40-position of the biaryl acid scaffold.
Due to its influence on potency, this benzoyl group
was incorporated into the 40-position of the 5-aryl 1-
methyl-pyridone scaffold reported here to give 17 (61%
inhibition of type 1 SR activity at 10 lM). Whilst not
as potent as 5b, the inhibitory activity of 17 suggests that
the benzoyl group is tolerated by the enzyme active site
of both isozymes.
N,N-Diisopropyl-2-(4-(1-methyl-6-oxopiperidin-3-yl)phen-
1
oxy)acetamide (15). H NMR (CD3OD, 500 MHz) d
1.24 (d, 6H, J = 6.4 Hz, (CH3)2), 1.38 (d, 6H,
J = 6.8 Hz, (CH3)2), 2.02 (m, 2H, NCH3CH2), 2.46 (m,
2H, COCH2CH2), 2.94 (s, 3H, NCH3), 3.09 (m, 1H,
NCH3CH2CH), 3.41 (m, 2H, COCH2CH2), 3.54 (m,
1H, CH(CH3)2), 4.09 (m, 1H, CH(CH3)2), 4.67 (s, 2H,
OCH2), 6.92 (d, 2H, J = 8.8 Hz, ArH), 7.23 (d, 2H,
J = 8.3 Hz, ArH). HRMS (M+H). Found: 347.2327
(Calcd for C20H31N2O3: 347.2335).
The presence of a long carbon chain tether enhanced the
inhibitory activity of compounds 26 and 27 (43% and
33% inhibition of type 1 activity, respectively) in com-
parison to 14 (6% inhibition of type 1 activity). This
result provides further evidence for the presence of a
lipophilic pocket in the enzyme active site that tolerates
bulky hydrophobic groups at the terminus of the inhib-
itor which is not interacting with residues responsible for
the enzyme catalysed reduction. These compounds also
suggest a way forward for gold surface attachment to
facilitate potential biomolecular recognition studies.
1-Methyl-5-(4-(2-phenylacetyl)phenyl)pyridin-2(1H)-one
1
(17). H NMR (DMSO-d6, 500 MHz) d 3.62 (s, 3H,
NCH3), 4.49 (s, 2H, CH2), 6.61 (d, 1H, J = 9.8 Hz,
COCH@CH), 7.38 (m, 5H, ArH), 7.85 (d, 2H,
J = 8.3 Hz, ArH), 8.02 (dd, 1H, J = 2.7, 9.7 Hz,
COCH@CH), 8.18 (d, 1H, J = 8.3 Hz, ArH), 8.41 (d,
1H, J = 2.9 Hz, NCH3CH). HRMS (M+H). Found:
304.1340 (Calcd for C20H18NO2: 304.1338).
The results reported here reveal important information
on the correlation between SAR from 40-substituted
bicyclic pyridones (as described here) and SAR derived
from known 40-substituted biaryl acids, in particular
5a and 5b. We can conclude for the bicyclic pyridone
inhibitors, SAR for 40-substituents do not correlate with
N,N-Diisopropyl-2-(4-(2-methyl-4-oxo-3,4-dihydropyridin-
1(2H)-yl)phenoxy) acetamide (20). H NMR (CD3OD,
500 MHz) d 1.25 (d, 3H, J = 6.3 Hz, NCHCH3), 1.25
(d, 6H, J = 6.3 Hz, CH(CH3)2), 1.40 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 2.30 (dd, 1H, J = 3.2, 16.6 Hz, COCHaHb),
1

A. R. McCarthy et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3603–3607
3607
3.00 (dd, 1H, J = 6.8, 16.6 Hz, COCHaHb), 3.56 (m, 1H,
CH(CH3)2), 4.08 (m, 1H, CH(CH3)2), 4.37 (m, 1H,
NCHCH3), 4.72 (s, 2H, OCH2), 5.09 (d, 1H, J = 7.8 Hz,
COCH@CH), 7.01 (d, 2H, J = 9.3 Hz, ArH), 7.24 (d,
2H, J = 8.8 Hz, ArH), 7.53 (d, 1H, J = 7.8 Hz,
COCH@CH). HRMS (M+H). Found: 345.2188 (Calcd
for C20H29N2O3: 345.2178).
J = 4.8 Hz, OCH2), 4.51 (s, 2H, OCH2CO), 5.57 (m, 2H,
CH2CH@CH), 5.95 (s(br), 1H, NHCH2CH2), 6.64 (d,
1H, J = 9.5 Hz, COCH@CH), 6.67 (s(br), 1H,
NHCH2CH@CH), 6.96 (d, 2H J = 8.7 Hz, ArH), 7.35
(d, 2H, J = 8.7 Hz, ArH), 7.44 (d, 1H, J = 2.8 Hz,
NCH3CH), 7.57 (dd, 1H, J = 2.8, 9.5 Hz, COCH@CH).
HRMS (M+H). Found: 770.4426 (Calcd for
C42H64N3O8S: 770.4414).
N-Allyl-2-(4-(2-methyl-4-oxo-3,4-dihydropyridin-1(2H)-
yl)phenoxy)acetamide (21). 1H NMR (CD3OD,
500 MHz) d 1.25 (d, 3H, J = 6.4 Hz, CHCH3), 2.31 (dd,
1H, J = 2.9, 16.6 Hz, COCHaHb), 3.01 (dd, 1H, J = 6.4,
16.6 Hz, COCHaHb), 3.88 (d(br), 2H, J = 4.9 Hz,
NHCH2), 4.39 (m, 1H, CHCH3), 4.55 (s, 2H, OCH2),
5.10 (d, 1H, J = 7.3 Hz, COCH@CH), 5.12 (m, 2H,
CH2CH@CH2), 5.84 (m, 1H, CH2CH@CH2), 7.06 (d,
2H, J = 8.8 Hz, ArH), 7.26 (d, 2H, J = 9.2 Hz, ArH),
7.54 (d, 1H, J = 7.8 Hz, COCH@CH). HRMS (M+H).
Found: 301.1546 (Calcd for C17H21N2O3: 301.1552).
References and notes
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Mol. Biol. 2004, 88, 1.
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4. Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.;
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5. Lamb, J. C.; Levy, M. A.; Johnson, R. K.; Issacs, J. T.
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A.; Neubauer, B. L.; Pike, A. J.; Pennington, P. A.;
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7. Abell, A. D.; Brandt, M.; Levy, M. A.; Holt, D. A. Bioorg.
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15. Reichert, W.; Hartmann, R. W.; Jose, J. J. Enzyme Inhib.
2001, 16, 47.
2-(16-(Acetylthio)hexadecanamido)ethyl 6-(2-(4-(1-
methyl-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)acetam-
1
ido)hex-4-enoate (26). H NMR (CDCl3, 500 MHz) d
1.29 (m(br), 22H, (CH2)11), 1.56 (m, 4H, (CH2)2), 2.16
(t, 2H, J = 7.5 Hz, CH2), 2.30 (s, 3H, CH3CO), 2.40
(m, 4H, COCH2CH2), 2.83 (t, 2H, J = 7.1 Hz, CH2),
3.48 (m, 2H, NHCH2CH2), 3.60 (s, 3H, NCH3), 3.90
(t, 2H, J = 5.9 Hz, NHCH2CH=CH), 4.14 (t, 2H,
J = 5.2 Hz, NHCH2CH2), 4.50 (s, 2H, OCH2CO), 5.56
(m, 2H, CH2CH=CH), 5.96 (s(br), 1H, NHCH2CH2),
6.64 (d, 1H, J = 9.5 Hz, COCH@CH), 6.71 (s(br), 1H,
NHCH2CH@CH), 6.95 (d, 2H, J = 8.7 Hz, ArH), 7.34
(d, 2H, J = 8.7 Hz, ArH), 7.44 (d, 1H, J = 2.4 Hz,
NCH3CH), 7.57 (dd, 1H, J = 2.4, 9.5 Hz, COCH@CH).
HRMS (M+H). Found: 726.4182 (Calcd for
C40H60N3O7S: 726.4152).
2-(2-(16-(Acetylthio)hexadecanamido)ethoxy)ethyl 6-(2-
(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)acet-
amido)hex-4-enoate (27). 1H NMR (CDCl3, 500 MHz) d
1.28 (m(br), 20H, (CH2)10), 1.58 (m, 6H, (CH2)3), 2.16 (t,
2H, J = 7.5 Hz, CH2), 2.31 (s, 3H, CH3CO), 2.40 (m, 4H,
COCH2CH2), 2.84 (t, 2H, J = 7.5 Hz, CH2), 3.43 (m, 2H,
NHCH2CH2), 3.53 (t, 2H, J = 5.2 Hz, NHCH2CH2), 3.61
(s, 3H, NCH3), 3.63 (t, 2H, J = 4.8 Hz, OCH2), 3.92 (t,
2H, J = 5.9 Hz, NHCH2CH@CH), 4.21 (t, 2H,
16. Hartmann, R. W.; Reichert, M. Arch. Pharm. Pharm.
Med. Chem. 2000, 335, 145.