Novel amides and esters prodrugs of olmesartan: Synthesis, bioconversion, and pharmacokinetic evaluation

Article abstract of DOI:10.1016/j.bmcl.2010.07.089

Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.

Full text of DOI:10.1016/j.bmcl.2010.07.089

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5895–5899
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel amides and esters prodrugs of olmesartan: Synthesis, bioconversion,
and pharmacokinetic evaluation
Jin-Hun Park a,e, Jeong-Soo Chang c, Mohammed I. El-Gamal a,b, Won-Kyoung Choi a, Woong San Lee a,
Hye Jin Chung a, Hyun-Il Kim d, Young-Jin Cho d, Bong Sang Lee d, Hong-Ryeol Jeon d, Yong Sup Lee e,
Young Wook Choi c, Jaehwi Lee c, Chang-Hyun Oh a,b,
*
a Biomaterials Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
b Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea
c Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong, Dongjak-gu, Seoul 156-756, Republic of Korea
d CTCBIO Inc. 450-34, Noha-ri, Paltan-myeon, Hwaseong-si, Gyeonggi-do 445-913, Republic of Korea
e Department of Pharmaceutical Science, College of Pharmacy & Department of Life and Nanopharmaceutical Science, Kyung Hee University, 1 Hoegi-dong Dongdaemoon-ku,
Seoul 130-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat
plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone
moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa
were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a
promising prodrug of olmesartan.
Received 7 April 2010
Revised 6 July 2010
Accepted 21 July 2010
Available online 25 July 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Antihypertensive
Olmesartan
Olmesartan medoxomil
Prodrug
Amide
Ester
Pharmacokinetics
Hypertension is a disease which affects an estimated one billion
people worldwide.1 It is a serious disease with a momentous im-
pact on health and life expectancy. Controlling blood pressure
and prevention of its complications such as coronary heart disease,
renal failure, and cerebral vascular disease are the main objectives
for the treatment of hypertension.2
The renin–angiotensin aldosterone system (RAAS) is a very
complex system that plays an important role in the regulation of
blood pressure. Angiotensin II, the primary effector hormone of
RAAS, affects the cardiovascular system by influencing the vascular
tone, fluid volume, and electrolyte balance.3,4
There are many antihypertensive drugs available, many of
which act on the RAAS system. Angiotensin receptor blockers
(ARBs) are a class of antihypertensive agents that are growing in
popularity due to their excellent blood pressure control potential,
low adverse event profile, and high patient tolerability.5 Olmesar-
tan is an example of ARBs which acts by blocking type 1 angioten-
sin II receptors (AT1-R), leading to blocking of vasoconstriction,
reduction of sodium and water retention, and decrease of cellular
proliferation and hypertrophy.6 Besides AT1-R blockade, olmesar-
tan is assumed to exhibit an angiotensin-converting enzyme
(ACE) inhibitory action, prevent an increase in angiotensin II level,
and protect cardiovascular remodeling through an increase in car-
diac nitric oxide production and endogenous angiotensin-(1–7) via
over-expression of ACE2.7
The once daily dosing interval of most ARBs helps enhance
patient compliance which may lead to better patient outcomes.5
Olmesartan medoxomil is an ester prodrug of olmesartan which
showed potent and long-lasting antihypertensive activity by oral
administration.8 Olmesartan medoxomil is rapidly de-esterified
by an enzyme, arylesterase, which is located in both the intestine
and plasma.6 Figure 1 illustrates the enzymatic hydrolysis of olme-
sartan medoxomil into the active metabolite, olmesartan.9
In the present investigation, we report the design, synthesis, and
biological evaluation of novel amides and esters prodrugs of olme-
sartan. The medoxomil moiety of olmesartan medoxomil was mod-
ified in different ways. Substitution of the dioxolone ring with a
lipophilic n-octyl group instead of methyl group (compound IIa),
ring expansion and isosteric substitution of the methyl-substituted
* Corresponding author. Tel.: +82 2 958 5160; fax: +82 2 958 5189.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.07.089

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J.-H. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5895–5899
N
N
OH
OH
+
N
N
H2O
CO2
O
OH
O
O
O
O
O
N
N
N
N
O
Enzymatic Hydrolysis
N
N
N
N
O
H
H
Diacetyl
Olmesartan medoxomil
Ester Prodrug
Olmesartan
Active metabolite
Figure 1. Hydrolysis of olmesartan medoxomil to olmesartan.
five-membered dioxolone moiety with a six-membered uracil ring
(compound IIb), replacement with n-octyl group (compound IIc), or
ring opening and insertion of some isosteres (compounds Ia–c and
IId–f) were performed. Moreover, the ester moiety of olmesartan
medoxomil was retained in compounds IIa–f but replaced with
an isosteric amide moiety in compounds Ia–c. Our target is to im-
prove the pharmacokinetic properties of olmesartan, and hence,
the antihypertensive outcomes. The synthetic and screening proto-
cols are illustrated in details.
For the synthesis of the target compounds Ia–c and IIa–f, it was
important at the beginning to prepare the key carboxylic acid com-
pound, trityl olmesartan 3, as illustrated in Scheme 1. N-alkylation
of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-car-
boxylate (1) with 5-(40-bromomethyl-biphenyl-2-yl)-1-trityl-1H-
tetrazole afforded the ethyl ester of trityl olmesartan 2. Alkaline
hydrolysis of the ethyl ester moiety of 2 followed by acidification
of the formed potassium salt furnished trityl olmesartan 3.10
For the synthesis of the target ester compound IIa, it was essen-
tial to prepare the corresponding alkyl halide, 4-(bromomethyl)-5-
octyl-1,3-dioxol-2-one (12). Compound 12 was successfully pre-
pared according to the sequence of reactions illustrated in Scheme
2. Nonanoic acid (4) was converted into the corresponding acid
chloride 5 by refluxing in thionyl chloride.11 Acylation of Mel-
drum’s acid with the acid chloride 5 in the presence of pyridine
gave the corresponding acyl Meldrum’s acid, which underwent
alcoholysis with benzyl alcohol to give the corresponding b-keto
ester 6.12 Diazotization of 6 with TsN3 in the presence of TEA gave
the corresponding azo compound 7, which was treated with
rhodium acetate dimer to produce the corresponding
a-hydroxy-
b-keto ester 8. Cyclization of 8 with carbonyldiimidazole afforded
benzyl 5-octyl-2-oxo-1,3-dioxole-4-carboxylate (9), which upon
hydrogenolysis in the presence of Pd(OH)2 gave the corresponding
carboxylic acid derivative 10. Reduction of the carboxylic acid
group of 10 to produce the corresponding primary alcohol 11
N
N
N
N
N
b
a
OH
OH
OH
HN
OH
O
O
O
O
O
N
N
N
N
N
N
N
N
Tr
Tr
1
2
3
Scheme 1. Reagents and conditions: (a) 5-(40-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole, K2CO3, acetone, DMAc, reflux, 10 h, 75%; (b) (i) KOH, isopropanol, 60 °C, 4 h;
(ii) HCl, workup, 90%.
O
O
O
O
O
O
O
O
b
a
c
d
H3C(CH2)7
OH
H3C(CH2)7
OBn
H3C(CH2)7
OBn
H3C(CH2)7
Cl
H3C(CH2)7
OBn
N2
OH
4
5
6
8
7
H3C(CH2)7
HO
H3C(CH2)7
BnO
H3C(CH2)7
H3C(CH2)7
HO
O
O
O
O
O
O
O
O
O
O
f
O
O
h
e
g
Br
O
O
9
12
11
10
Scheme 2. Reagents and conditions: (a) SOCl2, reflux, 4 h, 99%; (b) (i) Meldrum’s acid, C5H5N, CH2Cl2, 0 °C, 2 h; (ii) BnOH, CH3CN, reflux, 9 h; (c) TsN3, TEA, CH3CN, 0 °C, 8 h,
99%; (d) Rh2(OAc)4, THF/H2O, reflux, 2 h, 50%; (e) CDI, DIPEA, THF, 0 °C, 8 h, 60%; (f) Pd(OH)2, H2, EtOH, 1 h, 94%; (g) (i) oxalyl chloride, DMF, CH2Cl2, 0 °C, 1.5 h
(ii) (n-Bu)4NBH4, CH2Cl2, ꢀ78 °C, 1 h, 60%; (h) CBr4, PPh3, CH2Cl2, 0 °C, 0.5 h, 79%.

J.-H. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5895–5899
5897
was carried out by using oxalyl chloride in the presence of DMF in
CH2Cl2 at 0 °C. Bromination of 11 with CBr4/PPh3 in CH2Cl2 gave the
target bromomethyl reagent 12.
Detritylation of 20a,b with concd HCl gave the target amide deriv-
atives Ia,b. Upon detritylation of 20b, the ethyl ester moiety was
simultaneously hydrolyzed to give the corresponding carboxylic
acid Ib (Scheme 5).
We tried to synthesize the (2-(2-hydroxyethylamino)ethyl)
amide derivative Ic by the same procedure utilized for synthesis
of Ia,b but these trials failed. Compound Ic was successfully
synthesized by another procedure as illustrated in Scheme 6. The
lactone derivative 21 was prepared by heating 3 with 2-(2-amino-
ethylamino)ethanol in the presence of HOBt, EDCI, and TEA in
anhydrous DMF. Detritylation and amide formation were achieved
in one step by refluxing 21 with 2-(2-aminoethylamino)ethanol in
dry acetonitrile.
Interaction of the commercially available 1,6-dibromohexane
(13) with NaNO2 (0.86 equiv) in DMSO afforded 1-bromo-6-nitro-
hexane (14), which was purified by fractional distillation.13 The
bromo group of 14 was substituted with azido group using sodium
azide to give 15. Treatment of the azido compound 15 with PPh3/
H2O in THF produced 6-nitrohexan-1-amine (16) (Scheme 3). Com-
pounds 14 and 16 were utilized for the synthesis of the target com-
pounds IId and Ia, respectively.
Synthesis of ethyl 7-aminoheptanoate (19) was carried out by
the same procedure as described for the preparation of 16 starting
with ethyl 7-bromoheptanoate (17) (Scheme 4). Compounds 19
was utilized for the synthesis of the target compound Ib.
Condensation of trityl olmesartan 3 with amine derivative 16 or
19 in the presence of HOBt, EDCI, and TEA in anhydrous DMF affor-
ded the corresponding trityl olmesartan amide derivatives 20a,b.
The target ester compounds IIa–f were synthesized by esterifi-
cation of the carboxylic acid group of 3 with the appropriate alkyl
halide, and subsequent detritylation using concd HCl. Detritylation
of 22e lead to simultaneous hydrolysis of the terminal ester group
to give a mixture of terminal ester IIe and terminal acid IIf
b
a
c
Br(CH2)6Br
Br(CH2)6NO2
N3(CH2)6NO2
NH2(CH2)6NO2
16
15
14
13
Scheme 3. Reagents and conditions: (a) NaNO2, DMSO, rt, 1 h, 30%; (b) NaN3, DMF, rt, 12 h, 95%; (c) PPh3, H2O, THF, rt, 3 days, 85%.
a
b
Br(CH2)6COOEt
N3(CH2)6COOEt
NH2(CH2)6COOEt
18
17
19
Scheme 4. Reagents and conditions: (a) NaN3, DMF, rt, 12 h, 95%; (b) PPh3, H2O, THF, rt, 7 h, 90%.
N
N
N
OH
OH
OH
OH
H
H
N
N
N
N
N
R
R
O
O
O
a
b
N
N
N
N
N
N
N
N
N
N
N
H
N
Tr
Tr
Ia,b
Ia: R = (CH2)6NO2
3
20a,b
20a: R = (CH2)6NO2
20b: R = (CH2)6COOEt
Ib: R = (CH2)6COOH
Scheme 5. Reagents and conditions: (a) appropriate amine, HOBt, EDCI, TEA, DMF, rt, 6 h, (20a: 60%, 20b: 55%); (b) concd HCl, acetone, H2O, rt, 2 h, (Ia: 80.1%, Ib: 82%).
N
OH
N
N
N
N
OH
O
N
OH
H
N
a
O
OH
N
H
O
b
O
N
N
N
N
N
N
N
N
N
N
Tr
N
Tr
N
H
21
Ic
3
Scheme 6. Reagents and conditions: (a) NH2(CH2)2NH(CH2)2OH, HOBt, EDCI, TEA, DMF, 60 °C, 5 h, 75%; (b) NH2(CH2)2NH(CH2)2OH, CH3CN, reflux, 24 h, 53.7%.

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J.-H. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5895–5899
N
N
N
OH
OH
OH
OH
N
N
N
O
O
R
R
O
a
O
O
b
N
N
N
N
N
N
N
N
N
N
N
Tr
N
H
Tr
3
22a-e
IIa-f
H3C(CH )
2 7O
H3C(CH2)7
O
22a: R =
22b: R =
IIa: R =
O
O
O
O
O
O
NH
NH
NH
NH
O
O
IIb: R =
22c: R = (CH2)7CH3
22d: R = (CH2)6NO2
IIc: R = (CH2)7CH3
IId: R = (CH2)6NO2
22e: R = (CH2)6COOEt
IIe: R = (CH2)6COOEt
IIf: R = (CH2)6COOH
Scheme 7. Reagents and conditions: (a) R-X, K2CO3, KI, DMAc, 70 °C, 2 h, (22a: 76%, 22b: 68.3%, 22c: 72%, 22d: 64%, 22e: 75%); (b) concd HCl, acetone, H2O, rt, 2 h, (IIa: 68%,
IIb: 93.7%, IIc: 91%, IId: 93%, IIe: 26.6%, IIf: 30%).
derivatives which were separated by column chromatography
(Scheme 7).
tion–time profiles of olmesartan after oral administration of IIa
and olmesartan medoxomil in rats are shown in Figure 2, and some
relevant pharmacokinetic parameters of olmesartan are summa-
rized in Table 2. After oral administration, olmesartan was detected
in plasma from the first blood sampling time, 30 min. Compound
IIa was well absorbed from rat gastrointestinal tract and rapidly
converted into the active form. After administration of prodrug
IIa, both the Cmax and AUC0–last of olmesartan were significantly
greater (128% and 95.1% increase, respectively) than those ob-
served after administration of olmesartan medoxomil. The results
indicated that introduction of long aliphatic chain enhanced the
oral absorption and systemic exposure level of olmesartan. These
effects are possibly due to a marked increase in lipophilicity of
IIa induced by long aliphatic chain over olmesartan medoxomil.
In conclusion, we designed and synthesized a series of novel
amides and esters prodrugs of olmesartan. We studied the
in vitro metabolic stability of the newly synthesized compounds
in comparison with olmesartan medoxomil. In addition, the
The stabilities of all compounds were determined in rat plasma
in vitro. The remaining percentages of the compounds in rat plas-
ma after the incubation were summarized in Table 1. After the
30 min incubation period of IIa, the prodrug peak disappeared,
and the olmesartan peak was increased. The results showed that
compound IIa was rapidly hydrolyzed to olmesartan, active metab-
olite, in plasma. Based on stability testing results, pharmacokinet-
ics study was conducted to determine whether IIa was converted
into olmesartan in vivo. The prodrug IIa was administered orally
using a feeding tube to male Sprague–Dawley rats at a dose of
20 mg/kg as olmesartan. The plasma concentrations of olmesartan
were determined by a slight modification of the reported liquid
chromatography-tandem mass spectrometric method.14 The total
area under the plasma concentration–time curve from time zero
to the last measured time (AUC0–last) was calculated by the linear
trapezoidal rule method.15 The mean arterial plasma concentra-
Table 1
In vitro stability of compounds Ia–c and IIa–f in rat plasma
Structure
Compound No.
R
Stability (% remaining)
Ia
Ib
Ic
–NH(CH2)6NO2
–NH(CH2)6COOH
–NH(CH2)2NH(CH2)2OH
100.7
97.5
N
N
OH
R
98.9
NAa
O
O
O
O
IIa
O
N
N
(CH2)7CH3
H
N
N
O
N
O
H
IIb
96.3
O
NH
IIc
IId
IIe
IIf
–O(CH2)7CH3
–O(CH2)6NO2
–O(CH2)6COOC2H5
–O(CH2)6COOH
90.2
100.2
81.1
98.8
NAa
Olmesartan medoxomil
To determine the plasma stability, 50
lg/mL compound in rat plasma was incubated for 30 min at 37 °C.
a
NA, not applicable.

J.-H. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5895–5899
5899
synthesized ester prodrug IIa with n-octyl substituted dioxolone
ring is proposed to be an effective prodrug of olmesartan with im-
proved oral bioavailability. Further modification of this compound
in order to improve the pharmacokinetic properties and oral bio-
availability of olmesartan is currently in progress. Our ultimate
goal is to improve the antihypertensive impact of olmesartan.
Acknowledgments
We thank Dr. Hong-Ryeol Jeon, CTCBIO Inc., Republic of Korea,
for financial support and for performing the biological experi-
ments.
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Table 2
Pharmacokinetic parameters (mean SD) of olmesartan after oral administration of
prodrugs (20 mg/kg as olmesartan) to male Sprague–Dawley rats Cmax, peak plasma
concentration; Tmax
, time to reach Cmax; AUC0–last, total area under the plasma
concentration–time curve from time zero to last measured time
Parameter
Olmesartan medoxomil (n = 4)
IIa (n = 4)
Cmax (ng/mL)
Tmax (h)
AUC0–last (ng h/mL)
125 72.5
0.5–3
285 95.9
1–3
569 269
1110 140
14. Lee, B. S.; Kang, M. J.; Choi, W. S.; Choi, Y. B.; Kim, H. S.; Lee, S. K.; Lee, J.; Choi, Y.
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in vivo pharmacokinetic parameters of compound IIa were studied
and compared with those of olmesartan medoxomil. The newly