Synthesis and relative bioavailability of meptazinol benzoyl esters as prodrugs

Article abstract of DOI:10.1016/j.bmcl.2005.03.039

Three meptazinol benzoyl esters (1-3) were synthesized as prodrugs to minimize the first-pass effect of meptazinol and improve the bioavailability. Among these three esters, compound 3 showed better bioavailability than the parent meptazinol. Further, the

Full text of DOI:10.1016/j.bmcl.2005.03.039

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2607–2609
Synthesis and relative bioavailability of
meptazinol benzoyl esters as prodrugs
Meiyan Lu, Chengji Zhang, Jinglai Hao and Zhuibai Qiu*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China
Received 4 February 2005; revised 2 March 2005; accepted 10 March 2005
Available online 9 April 2005
Abstract—Three meptazinol benzoyl esters (1–3) were synthesized as prodrugs to minimize the first-pass effect of meptazinol and
improve the bioavailability. Among these three esters, compound 3 showed better bioavailability than the parent meptazinol. Fur-
ther, the relative regional bioavailability of prodrug 3 was evaluated using in situ closed loop study in rats, which showed that pro-
drug 3 has higher absorption efficacy in rat intestine. Thusly, prodrug 3 may be worth for further development.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Known as a partial opioid agonist, meptazinol (3-(3-eth-
ylhexahydro-1-methyl-1H-azepin-3-yl) phenol) was used
clinically for short-term relief of moderate to severe pain
(e.g., the pain of childbirth, injury or surgery). Unlike
other typical opiates such as morphine and fentanyl, it
accompanies less respiratory depression and addictive
potential. Meptazinol was commercially available since
1989 and embodied in British Pharmacopoeia in 1998.
New clinical applications, pharmacophores, and analge-
sic mechanism of meptazinol were reported recently1–6
both from our group and other researchers.
N
Meptazinol
OH
However, meptazinol displayed poor oral bioavailability
(8.69%) because of serious first-pass effect in liver similar
O
N
O
Meptazinol
Meptazinol
Cl
O
O
1
O
N
O
O
H
N
H
O
N
H
2
CH3
CH3
N
COOH
O
CH3
COOH
NH2
Meptazinol
+
O
Cl
O
H
N
H
Fmoc
O
N
H
3
Scheme 1. Synthetic route to the target compounds.
Keywords: Meptazinol; Prodrug; Benzoic ester; Analgesic.
*
Corresponding author. Tel.: +86 21 54237595; fax: +86 21 54237264; e-mail: zbqiu@shmu.edu.cn
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.039

2608
M. Lu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2607–2609
Table 1. Analgesic activity of objective compounds
enhance hydrophobicity as well to improve its pharma-
cokinetic properties. In the present study, three benzoyl
ester derivatives (prodrugs 1–3) of meptazinol were pre-
pared to improve its relative bioavailability and reduce
the first-pass effect.
Sample
Analgesic activity
Hot-plate test
Acetylcholine induced mice
writhing test
Ip 100 lmol/kg
Ig 50 lmol/kg
After 40 min
After 80 min
As outlined in Scheme 1, 1 and 2 were prepared simply
by condensing meptazinol with benzoic chloride and isa-
toic anhydride, with 58% and 22% yield, respectively.
Protection of the amine group of (2-amine-6-methyl)
benzoic acid with 9-fluorenylmethoxycarbonyl chloride
(Fmoc-Cl) followed by coupling with meptazinol in
the presence of dicyclohexylcarbodiimide (DCC) and
4-dimethylaminopyridine (DMAP) gave meptazinol
(20-amine-60-methyl) benzoyl ester (prodrug 3) in about
64% yield.9 We chose Fmoc as a protecting group simply
because it has been widely used as an amine protective
group in many coupling reactions in peptide related
chemistry. The structures of these prodrugs and their
Meptazinola
5/10
4/10
3/10
4/10
2/10
1/10
1/10
2/10
0/10
1
2
a Testified as the control.
1
hydrochloride salts were determined by H NMR, MS,
and HRESI.
Prodrugs 1 and 2 hydrochlorides were administrated by
intraperitoneal and intragastric administration to Kun-
ming white mice. The analgesic potency was determined
by hot-plate and acetylcholine induced mice writhing as-
says (Table 1). However, both prodrugs showed similar
analgesic potency and duration with that of meptazinol.
A possible explanation was that these esters were easy to
hydrolyze in acidic circumstance of the stomach.
Given this consideration, (2-amine-6-methyl)-benzoic
acid meptazinol ester (prodrug 3) was further designed
and prepared. As shown in the 3D molecular modeling
structures using SYBYL 6.9 (Tripos Inc., 1699 South
Handley Rd, Suite 303, St. Louis, MO 63144) (Fig. 1),
the carbonyl group of prodrug 3 is surrounded by both
the 20-amino group and the 60-methyl group which could
thusly protect the ester bond from hydrolysis.
It is interesting to note that unlike other two meptazinol
prodrugs (compounds 1 and 2), prodrug 3 showed sig-
nificant improvement in bioavailability assays compar-
ing to the parent meptazinol (Table 2).10 Since good
correlation between meptazinol analgesic potency and
plasma concentration was observed by Franklin
et al.,10 it was of considerable interest to further investigate
prodrug 3Õs specific regions absorption in intestine and
local metabolism. The results were displayed in Table
3 and Figure 2. Prodrug 3 showed significant increase
in looped duodenum, jejunum, and colon absorption
than the control. Especially it showed more than 10-fold
absorption in duodenum than meptazinol.
Figure 1. 3D structure models of three prodrugs.
to other opiates with a phenol group.7 Furthermore,
good correlation between meptazinol analgesic potency
and plasma concentration was observed by Franklin
et al.8 Thusly, masking of this phenol group with esters
could protect this drug from enzyme metabolism, and
Table 2. Relative bioavailability of prodrugs 1–3
F (%)
Pa
1
2
3
4
5
6
Mean
SD
Prodrug 1
Prodrug 2
Prodrug 3
58.07
101.04
174.27
53.89
183.64
120.08
111.90
106.71
135.88
81.61
81.90
167.97
75.38
59.82
129.94
133.23
80.36
149.21
85.68
102.25
146.22
24.59
28.62
21.56
0.1206
0.6150
0.0021
a Statistical P value. P > 0.05, no statistical significance. P < 0.01, statistical significance.

M. Lu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2607–2609
2609
Table 3. Relative bioavailability of prodrug 3 hydrochloride into
closed loop stomach, duodenum, jejunum or colon of each rat
Acknowledgements
This project was supported by National Natural Science
Foundation of China (No. 30271539, 2003–2005), and
the analgesic assays were performed by Shanghai Insti-
tute of Materia Medica.
Looped
part
F (%)
No. 1
50.12
Duodenum 1398.26 784.24 917.96 867.84 1024.39 276.35
No. 2 No. 3 No. 4 Mean
SD
27.86
Stomach
48.37
60.28 107.65
65.40
Jejunum
Colon
612.21 510.72 552.41 522.16
459.70 511.29 528.46 654.05
562.72
541.45
45.43
82.47
References and notes
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rosci. Lett. 2002, 329, 25–28.
4. Zhang, H.; Zhang, Y. Q.; Qiu, Z. B.; Zhao, Z. Q.
Neurosci. Lett. 2004, 356, 9–12.
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Physiol. Sin. 2004, 56, 295–300.
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Pharmacol. Sin 2005, 26, 334–338.
7. Norbury, H. M.; Franklin, R. A.; Graham, D. F. Eur. J.
Clin. Pharmacol. 1983, 25, 77.
8. Franklin, R. A.; Pierce, D. M.; Goode, P. G. J. Pharm.
Pharmacol. 1976, 28, 852–853.
0
0
T(h)
Colon
2
4
6
8
10
IG
Stomach
Duodenum
Jejunum
9. Spectral data of the selected compound. Prodrug 3
hydrochloride: 1HNMR (400 Hz, DMSO) d 9.88 (br s,
ꢀ1/2 H, NH+), 8.60 (br s, ꢀ1/2H, NH+), 7.50–7.42 (m,
1H, Ar-H), 7.33–7.09 (m, 4H, Ar-H), 6.69 (d, 1H, Ar-H),
6.50–6.47 (m, 1H, Ar-H), 4.01–3.97 (m, 1H, N-CH), 3.87
(br s, NHþ3 ), 3.62–3.58 (m, 1H, N-CH), 3.46–3.41 (q, 2H,
CH2CH3, J = 7.0), 3.18–3.14 (m, 2H, N-CH2), 2.86 (d, 3H,
N-CH3, J = 3.5), 2.47 (s, 3H, Ar-CH3), 1.84–1.46 (m, 4H,
CH2 · 2), 1.05 (t, 2H, CH2, J = 7.0 Hz), 0.56 (t, 3H,
CH2CH3, J = 7.3 Hz); ES-MS (m/z, M+) 366; HRMS
(ESI, M+1) calcd for C23H31N2O2: 367.2380. Found
367.2381.
Figure 2. Mean plasma meptazinol concentration after intra-stomach,
intra-duodenum, intra-jejunum, intra-colon administration of prodrug
3 at a dose of 92.8 lmol/kg.
In conclusion, we have synthesized three meptazinol
benzoyl esters as prodrugs to minimize the first-pass ef-
fect of meptazinol and to enhance the bioavailability.
Among the three prodrugs (1–3) that we prepared, pro-
drug 3 showed much higher absorption efficacy in rat
intestine comparing to meptazinol which correlated well
with its enhanced bioavailability. Thusly, it may be
worth for further development.
10. Wang X. L. MasterÕs paper of Fudan University. 2004; pp
20–54.