Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol

Article abstract of DOI:10.1016/j.bmcl.2005.08.016

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The

Full text of DOI:10.1016/j.bmcl.2005.08.016

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4953–4956
Design, synthesis, and bioavailability evaluation
of coumarin-based prodrug of meptazinol
Qiong Xie, Xiaolin Wang, Xinghai Wang, Zhiqiang Jiang and Zhuibai Qiu*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China
Received 5 May 2005; revised 18 July 2005; accepted 5 August 2005
Available online 9 September 2005
Abstract—Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic
ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavail-
ability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Acting as a mixed agonist/antagonist opioid analgesic,
meptazinol (( )-3-(3-ethyl-1-methyl-hexahydro-1H-aze-
pin-3-yl) phenol, 1) has been marketed by Wyeth for
the treatment of moderate to severe pain since 19831
and included in the British Pharmacopoeia in 1998.2 Un-
like other typical opiates, meptazinol showed less respi-
ratory depression and lower addictive potential.3–5
However, the clinical uses of meptazinol were still
restricted by its low oral bioavailability (8.69%).6 Simi-
lar to some drugs with phenol groups, meptazinol was
easily metabolized by enzymes in liver and caused seri-
ous first-pass effect. New clinical applications, pharma-
cophores, and analgesic mechanism of meptazinol
were reported recently7–10 both from QiuÕs group and
other researchers.
the parent drug and coumarin.29–31 The major outstand-
ing advantage of the prodrug system is that the hydroly-
sate coumarin has been found to be relatively nontoxic
in many clinical and laboratory studies.
It was of considerable interest to apply the coumarin-
based prodrug system for masking the phenol group of
meptazinol (1) for protection against the enzyme metab-
olism. Among the several previously reported carboxyl-
ated phenyl propenoic acid as masked coumarin
carriers, the propionyloxy group-substituted phenyl
propenoic acid (2) was specifically chosen as our carrier
molecule simply because it could be prepared mostly
efficiently among all the known acetyl, iso-propionyl,
and tert-butyryl coumarin carriers as described in the lit-
erature13 and the corresponding results of esterase kinet-
ics indicated that variations of the steric bulkiness of the
acyl group did not significantly affect the rate of the
release of the parent drug. Therefore, we designed and
synthesized meptazinol (Z)-3-[2-(propionyloxy)phenyl]-
2-propenoic ester (3) as a potential prodrug to explore
this potential. Coumarin was converted into (Z)-3-[2-
(propionyloxy)phenyl]-2-propenoic acid (2) in six steps
using a modification of literature procedures13 with the
total productivity of 20.4% (Fig. 1). The spectrum of
(2) has confirmed a Z-configuration of double bond
based on a J value of 12.2 Hz,32 which matched well
with the data reported in Ref. 13.
As part of a continuing effort in our laboratory to devel-
op novel meptazinol prodrugs as potential therapeutic
agents, Qiu and co-workers recently reported the syn-
thesis of three benzoyl esters (I–III) as meptazinol pro-
drugs. Among these three esters, analogue III showed
enhanced bioavailability presumably due to an en-
hanced lipophilicity and metabolic stability.11 A couma-
rin-based esterase-sensitive prodrug system and its
application for the preparation of prodrugs of amines
and cyclic prodrugs of peptides12–28 have been reported
recently. The design utilized an esterase-triggering intra-
molecular lactonization of cis-coumarinic acid to release
Coupling of meptazinol (1) with (Z)-3-[2-(propionyl-
oxy)phenyl]-2-propenoic acid (2) was accomplished in
the presence of 1,3-dicyclohexyl carbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) to give the
Keywords: Meptazinol; Coumarin-based prodrug; Synthesis;
Bioavailability.
*
Corresponding author. Tel.: +86 021 54237595; fax: +86 021
54237264; e-mail: zbqiu@shmu.edu.cn
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.016

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Q. Xie et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4953–4956
Figure 1. Synthesis of the carrier molecule (2). TBDMS, tert-butyldimethyl silyl; DMAP, 4-dimethylaminopyridine.
phenol ester (3) in 69% yield.33 The synthetic route is
outlined below (Fig. 2). The structures of the base and
hydrochloride of this prodrug were determined by
NMR, IR, and HR-ESI.34
As known to us, the prodrug can be hydrolyzed to mep-
tazinol by the plasma esterase in vitro after the blood
sample is collected, which can result in the concentration
of meptazinol determined to be higher than the actual
concentration. To prevent the above case occurring,
the esterase inhibitor Na2S2O5 was quantitatively added
to the plasma sample immediately after blood sample
was collected and centrifuged.36 The HPLC system
was optimized on Frost.37
As suggested by Franklin et al.35 a good correlation was
observed between meptazinolÕs analgesic potency and its
plasma concentration. Thus in our hand, oral bioavail-
ability, which in turn indicated the bioactivity, of the
prodrug and of the parent drug was measured in rats,
respectively.
Listed in Table 2 are the area under curve (AUC)
and absolute bioavailability (F%) of meptazinol via
intravenous (iv) versus intragastric (ig) administration
as well as that of the meptazinol prodrug via ig
administration. The corresponding mean plasma
meptazinol concentration–time curves are shown in
Figure 3.
The bioavailability evaluation was designed as a three-
way cross-over study. Six rats were divided into three
groups randomly and evenly. During each period, there
is a 7 daysÕ wash-out time. The routes of administration
in each period for each rat were listed in Table 1.
OH
HOOC
CH3CH2COO
CH3CH2COO
(1)DCC/DMAP
CH3
O C
+
N
O
(2)HCl-ether
CH3
N
HCl
3
2
1
Figure 2. Synthetic route of the meptazinol prodrug (3).
Table 1. The routes of administration in each period for each rat
No
1
2
3
4
5
6
Period I
Period II
Period III
A
B
C
A
B
C
B
C
A
B
C
A
C
A
B
C
A
B
A, iv 29.7 lmol/kg meptazinol; B, ig 92.8 lmol/kg meptazinol; C, ig 92.8 lmol/kg prodrug.
Table 2. AUC and absolute bioavailability of meptazinol and prodrug
(n = 6)
Meptazinol (iv)
29.7 lmol/kg
Meptazinol (ig)
92.8 lmol/kg
Prodrug (ig)
92.8 lmol/kg
Mean
1985.53
SD
Mean
SD
Mean
SD
AUC0!10 (ng h/ml)
533.82
712.63
12.12
118.69
3.57
2631.78
51.75
1385.30
32.99
F%a
a F% = (AUC0!10 (ig)/92.8)/(AUC0!10 (iv)/29.7).

Q. Xie et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4953–4956
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Figure 3. Mean plasma meptazinol concentration–time curves after iv
and ig administration of meptazinol and ig administration of prodrug
in rats.
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The absolute bioavailability of meptazinol prodrug (3)
via ig administration was 51.75% 32.99% (n = 6). This
indicated a more than 4-fold increase over the value ob-
tained for meptazinol, 12.12% 3.57%. Based on the
two sides t-test (P < 0.01), differences in the values of
AUC0!10 and F% between the two groups suggested
great statistical significance.
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propionyloxy)phenyl]-2-propenoic meptazinol ester
hydrochloride (3), was designed and synthesized to
minimize the first-pass effect of meptazinol and en-
hance the oral bioavailability. Biological evaluation
data indicated that there was a 4-fold increase in oral
bioavailability of this prodrug compared to the parent
drug meptazinol. This coumarin-based prodrug showed
a superior oral bioavailability to the earlier reported
meptazinol benzoyl esters.11 These results highlight
the potential of using coumarin-based esterase-sensitive
system as a prodrug template for other drug molecules
besides meptazinol.
30. Gudmundsson, O. S.; Vander Velde, D. G.; Jois, S. D.;
Bak, A.; Siahaan, T. J.; Borchardt, R. T. J. Pept. Res.
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Acknowledgment
31. Borchardt, R. T. J. Controlled Release 1999, 62, 231.
32. Spectral data of the carrier molecule (2): 1H NMR
(CDCl3) d 7.46 (d, 1H), 7.36 (t, 1H), 7.22 (t, 1H), 7.08
(d, 1H), 7.00 (d, 1H, J = 12.2 Hz), 6.05 (d, 1H,
J = 12.2 Hz), 2.58 (q, 2H, J = 7.6 Hz), 1.25 (t, 3H,
J = 7.6 Hz).
This project was supported by National Natural Science
Foundation of China (No. 30271539, 2003–2005).
References and notes
33. Synthesis of (Z)-3-[2-(propionyloxy)phenyl]-2-propenoic
meptazinol ester hydrochloride (3). A solution of 2
(0.73 g, 3.32 mmol) in dry CH2Cl2 (15 ml) was added
DCC (0.75 g, 3.64 mmol) at 0 ꢁC. After stirring for 10 min,
this was followed by the addition of 1 (0.70 g, 3.00 mmol)
in dry CH2Cl2 (40 ml) and DMAP (0.07 g, 0.57 mmol).
After stirring at 0 ꢁC for 2 h and at room temperature for
4 h, the solution was cooled below ꢀ20 ꢁC for 30 min and
filtered. The filtrate was acidified to pH 7.0 using 2.5%
acetic acid, then extracted with CH2Cl2 (5 ml). The
combined organic layer was dried over MgSO4 and
evaporated to give a brown oil (1.54 g). The oil was
chromatographed on a silica gel column to afford the
prodrug base as a yellow oil (0.90 g, 68.9%). To a solution
of the base (0.02 g) in dry ether (4 ml) was added HCl–
ether (0.3 ml) to modulate pH to 4. The solution was
concentrated and dried at room temperature to afford
hydrochloride 3 as a yellow solid (0.02 g, 92.3%).
34. Spectral data of the prodrug base and its hydrochloride
1. Med Actual/Drugs Today, 1983, 19, 415.
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Pharmacol. 1978, 9, 73.
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5. Holmes, B.; Ward, A. Drugs 1985, 30, 285.
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Neurosci. Lett. 2004, 356, 9.
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1
(3): Spectral data of the prodrug base: H NMR (CDCl3)

4956
Q. Xie et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4953–4956
d 7.60 (dd, 1H, J1 = 7.53 Hz, J2 = 1.37 Hz), 7.34 (dt, 1H,
NHCH2 · 2), 2.82 (m, 3H, N-CH3), 2.59 (q, 2H,
J = 7.42 Hz, COCH2CH3), 2.83–1.40 (m, 8H, CH2 · 4),
1.13 (t, 3H, J = 7.42 Hz, COCH2CH3), 0.49 (m, 3H,
CH2CH3). 13C NMR (DMSO-d6): d 171.2 (C@O), 162.8
(C@O), 149.6, 147.3, 144.8, 143.3, 138.4, 129.5, 128.9,
127.4, 124.9, 123.7 & 123.3, 121.9, 120.8, 119.7, 119.3,
66.0 & 62.8, 59.3 & 57.7, 47.1 & 46.3, 44.2 & 43.8, 36.0 &
35.3, 33.5 & 33.0, 26.9, 26.4 & 24.8, 20.7, 9.1, 8.3. HR-
ESI [M+1]+ calcd for C27H34NO4 436.24823, found
436.24848. FT-IR: 3404 (cN+H), 2937, 1758 (cC@O),
1606 (cphenyl), 1458, 1131 (cC–O–C), 950, 761,702.
35. Franklin, R. A.; Pierce, D. M.; Goode, P. G. J. Pharm.
Pharmacol. 1976, 28, 852.
J1 = 7.53 Hz, J2 = 1.37 Hz), 7.27 (m, 1H), 7.22 (dt, 1H,
J1 = 7.52 Hz, J2 = 1.02 Hz), 7.14 (m, 1H), 7.10 (dd, 1H,
J1 = 8.20 Hz, J2 = 1.02 Hz), 7.07 (d, 1H, J = 12.3 Hz, cis-
= CH · 1), 6.94–6.90 (m, 2H), 6.22 (d, 1H, J = 12.3 Hz,
cis- = CH · 1), 2.90 (m, 1H, NCH2), 2.72–2.65 (m, 2H,
NCH2), 2.60 (q, 2H, J = 7.52 Hz, COCH2CH3), 2.54–
2.48 (m, 1H, NCH2), 2.44 (s, 3H, N-CH3), 2.13–1.52 (m,
8H, CH2 · 4), 1.28 (t, 3H, J = 7.52 Hz, COCH2CH3),
0.60 (t, 3H, J = 7.52 Hz, CH2CH3). Spectral data of the
prodrug hydrochloride (3): 1H NMR (DMSO-d6): d
10.18 (br s, ꢁ1/2 H, N+–H, D2O exchange), 8.63 (br s,
ꢁ1/2 H, N+–H, D2O exchange), 7.60 (t, 1H, J = 7.42 Hz,
Ar-H), 7.45–7.38 (m, 2H, Ar-H · 2), 7.31–7.00 (m, 6H,
Ar-H · 5, cis- = CH · 1), 6.32 (dd, H, J1 = 4.3 Hz,
J2 = 12.1 Hz; cis- = CH · 1), 3.94–3.09 (m, 4H,
36. Hu, X. Y.; Liu, F.; Luo, Y. Yaowu Fenxi Zazhi (Chinese)
1997, 17, 124.
37. Frost, T. Analyst 1981, 106, 999.