The discovery and synthesis of potent zwitterionic inhibitors of renin

Article abstract of DOI:10.1016/j.bmcl.2011.02.067

The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.

Full text of DOI:10.1016/j.bmcl.2011.02.067

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2430–2436
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery and synthesis of potent zwitterionic inhibitors of renin
Renee Aspiotis a, , Austin Chen a, Elizabeth Cauchon a, Daniel Dubé a, Jean-Pierre Falgueyret a,
⇑
Sébastien Gagné a, Michel Gallant a, Erich L. Grimm a, Robert Houle a, Hélène Juteau a,
Patrick Lacombe a, Sébastien Laliberté a, Jean-François Lévesque a, Dwight MacDonald a,
Dan McKay a, M. David Percival a, Patrick Roy a, Stephen M. Soisson b, Tom Wu a
a Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8
b Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (rep-
resented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with
improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous
non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitter-
ions are also discussed within.
Received 11 January 2011
Accepted 15 February 2011
Available online 18 February 2011
Keywords:
Renin
Ó 2011 Elsevier Ltd. All rights reserved.
Hypertension
Piperidine
Zwitterion
hERG
CYP3A4
The renin-angiotensin-aldosterone system (RAAS) is an impor-
tant physiological regulator of blood pressure and fluid homeosta-
sis. The inhibition of either the formation or the action of
angiotensin (Ang) II, the main product of the RAAS, represents a
major therapeutic approach in the treatment of hypertension and
the prevention of associated comorbidities such as heart and kid-
ney failure, myocardial infarction, and stroke. Today, important
drugs modulating the RAAS include inhibitors of the angiotensin-
converting enzyme (ACE) and antagonists of the Ang II type-1
receptor (AT1R).1 It has long been hypothesized that inhibitors of
renin, the rate-limiting enzyme in the RAAS cascade responsible
for the cleavage of angiotensinogen to Ang I, may represent the
most attractive therapeutic strategy to block the RAAS.2
( Fig. 1), one of which culminated in the eventual disclosure of
aliskiren 1, the first and only direct renin inhibitor approved for
the treatment of essential hypertension.6
Concomitantly, the discovery of piperidine-based renin inhibi-
tors by Roche represents a more significant structural departure
from the original peptide-like molecules.7 Initially identified from
a high throughput screen,7b a series of optimizations, guided by
crystallography, led to the eventual identification of potent, orally
active, direct inhibitors of renin as in 2 (Fig. 1).7d Since then, several
potent piperidine-like analogues have been reported, including:
diazabicyclo-nonenes;8 achiral tetrahydropyridines;9 morphol-
ines;10 ketopiperazines;11 aminopropanamides;12 and non-chiral
indole-3-carboxamides.13
Initial efforts directed toward inhibiting renin involved scaf-
folds that were either peptide based or peptidomimetics.3 While
potency could be attained in the nanomolar range, the develop-
ment of these compounds were discontinued due to their meta-
bolic instability, excessive production costs and poor overall
pharmacokinetics (high clearance and low oral bioavailability).4
Nonetheless, these prototypical candidates were important in that
they were able to demonstrate a more effective blood pressure
lowering than an ACE inhibitor when dosed intravenously.5 By
the late 1990s, two new classes of non-peptidic inhibitors emerged
Recently, Actelion reported the discovery of a new series of po-
tent piperidine-based renin inhibitors bearing a 3-amido-4-aryl
substitution pattern with impressive anti-hypertensive effects
after oral administration in a double transgenic hypertensive rat
expressing human renin and angiotensinogen (e.g., 3, Fig. 1).14
Although many of these compounds were found to suffer from
time-dependent CYP3A4 inhibition (TDI), attempts to eradicate
these liabilities via the installation of polarity were met with only
modest success. Moreover, it was recently found that compound 3
exhibited undesirable affinity toward the hERG channel with a Ki
value of 243 nM (unpublished data). Herein, we wish to disclose
the discovery of potent, zwitterionic inhihitors of renin based on
the 3-amido-4-aryl substituted piperidine core, and our attempts
at addressing both CYP3A4 and hERG inhibition.
⇑
Corresponding author.
E-mail address: renee.aspiotis@sympatico.ca (R. Aspiotis).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.067

R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
2431
Cl
OMe
O
O
O
O
Me Me
OH
N
Me
Cl
OMe
MeO
Me Me
O
H
N
O
Cl
H2N
NH2
OH
MeO
O
O
N
O
O
N
H
N
H
MeO
Me
Me
1
Aliskiren
2
OMe
3
Figure 1. Non-peptidic inhibitors of renin.
Cl
O
O
N
Cl
Me
O
Cl
N
N
H
OMe
3
Figure 2. Modeling of compound 3 into active site of renin depicting site for water accessibility.
Given the promiscuous and hydrophobic nature of the CYP3A4
binding pocket15 and the fact that the hERG-encoded channel is
known to be blocked by lipophilic amines,16 we postulated that
the off-target activities observed with 3 were associated with its
chemical structure (i.e., cationic piperidine flanked by two lipo-
philic tails). Consequently, we set out to design new renin inhibi-
tors with added polarity. In order to ensure that these new
alterations would not jeopardize the intrinsic potency already real-
ized, we specifically opted to place a second polar appendage at the
meta-position of the benzyl amide ring in the renin S3 pocket, as
this was suggested by modeling to be an ideal place for attaching
a solvent exposed hydrophilic cap (Fig. 2).17
were either accessible from commercial sources or synthesized
from known literature procedures.
Table 1 highlights our initial modifications and their effect on
renin potency, hERG affinity and their potential for CYP3A4
time-dependent inhibition (TDI). We were pleased to see that all
of the analogues synthesized were highly potent on the renin en-
zyme, in agreement with our structural analysis of 3 in complex
with renin. Moreover, these compounds exhibited low nanomolar
activity in the presence of human plasma. Contrary to our initial
hypothesis however, many of the polar appendages had little effect
Guided by this hypothesis, we chose to work with the advanced
phenol intermediate 9, as this provided a suitable handle for rap-
idly introducing diverse hydrophilic attachments. The synthesis
of 9, which can be accessed in seven steps from commercial re-
agent 4, was prepared as shown in Scheme 1. Treatment of 3,5-
dibromophenol 4 with n-butyllithium and n-butylmagnesium
chloride followed by quenching with DMF afforded benzaldehyde
5. Subsequent coupling with commercially available 2-[(1E)-3-
methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
using standard Suzuki conditions followed by protection with
TBDMSCl afforded the aldehyde 6. The aldehyde was then sub-
jected to a stepwise reductive amination and the double bond re-
duced under standard balloon hydrogenation conditions to afford
benzyl amine 7. Amide coupling with acid 818 proceeded smoothly
without epimerization using HATU as the coupling agent, and sub-
sequent deprotection with TBAF yielded the desired phenol inter-
mediate 9. At this stage, phenol 9 could be derivatized to the
final analogues 13–18 via an alkylation, Mitsunobu, or an epox-
ide-ring opening reaction, followed by a BOC-deprotection. Unless
otherwise shown, the hydrophilic reagents used to functionalize 9
Table 1
Renin potency, hERG affinity, and NADPH-dependent CYP3A4 inhibition of select
renin compounds
a
Compd Renin IC50
(nM)
hERG Ki
M)
NADPH-dependent CYP3A4
inhibitionb
(l
Buffer Plasma
–NADPH
+NADPH
IC50
Shift
IC50
(lM)
IC50
(lM)
13
14
15
16b
16c
17
18a
18b
0.028
0.021
0.046
0.028
0.022
0.097
0.064
0.027
10.9
4.4
4.5
2.9
3.3
10.6
11.0
1.1
0.06
0.08
0.18
0.08
0.15
0.13
0.08
1.07
19.6
21.6
22.7
27.6
6.3
>50
19.3
>50
1.4
2.4
1.4
1.6
2.4
5.6
1.4
>50
14.1
9.0
16.1
16.8
2.6
>8.9
13.98
ꢀ1
a
Average of at least two replicates. See Ref. 12 for assay protocols.
NADPH dependent CYP3A4 inhibition: measures change in the IC50 for CYP3A4
30 min preincubation in the absence and presence of NADPH. IC50
b
during
a
shift P1.5-fold suggests that compound could be a potential TDI. Conversely, IC50
shift <1.5-fold signifies that the compound may not be a TDI. The higher the IC50
shift ratio, the greater the TDI potential. See Ref. 20 for complete protocol.

2432
R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
O
O
OTBS
OMe
OTBS
OMe
Br
OH
OH
HN
a
b, c
d, e
Br
Br
7
4
6
5
Cl
O
O
Cl
Me
: R1 = H, R2
=
13
CN
O
f, g
h, i
OH
14: R1 = H, R2 =CH2CH2OCH3
15: R1 = H, R2 = CH2CH2N(CH3)2
N
BOC
Cl
8
12
N3
MsO
O
16a: R1 = BOC, R2 = (CH2)3NH2
O
h, j
k, i
l, i
: R1 = H, R2
=
=
Cl
Me
16b
16c
(
CH2)3NHSO2CH3
: R1 = H, R2 (CH2)3NHC(O)NHEt
O
OR2
N
m, n, g
o, i
17: R1 = H, R2 = CH2C(CH3)2OH
N
R1
OMe
: R1 = H, R2
18b: R1 = H, R2
=
=
9: R1 = BOC, R2 = H
COOEt
COOH
18a
HO
COOEt
p
11
O
COOEt
(+/-)-trans
d (ii), q
10
Scheme 1. Reagents and conditions: (a) (i) n-BuLi (2.5 equiv), n-BuMgCl (0.6 equiv), toluene, ꢁ10 °C, 30 min; (ii) DMF (20 equiv), ꢁ40 °C to rt, 1 h; (b) 2-[(1E)-3-
methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 equiv), Na2CO3 (2 M in water, 4 equiv), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), DMF, 80 °C, 16 h;
(c) TBDMSCl, imidazole, DMF, rt, 16 h; (d) (i) cyclopropyl amine (2 equiv), MgSO4 (1.5 equiv), DCM, rt, 12 h; (ii) NaBH4 (1.5 equiv), MeOH, 0 °C to rt, 1.5–3 h; (e) H2 balloon,
10% Pd/C (10 mol %), EtOAc, rt, 1.5 h; (f) acid 8 (1 equiv), amine 9 (1 equiv), HATU (1.5 equiv), DIPEA (3 equiv), DCM, rt, 18 h; (g) TBAF (0.1 M, 1.3–2 equiv), THF, rt, 1 h; (h) RBr,
RCl or ROMs (1.3–2.5 equiv), Cs2CO3 or K2CO3 (1.3–4.4 equiv) DMF, 80 °C; (i) HCl (4 M in dioxane, 10 equiv), DCM, rt; (j) PPh3 (1.2 equiv), THF, H2O, 50 °C, 8 h; (k) MeSO2Cl
(1.2 equiv), Et3N (1.5 equiv), DCM, 0 °C, 2 h; (l) EtNCO (1.5 equiv), THF, 0 °C, 2 h; (m) Cs2CO3 (2 equiv), 2,2-dimethyloxirane (25 equiv), DMF, 50–80 °C, 22.5 h; (n) TMSI
(2 equiv), MeCN, 0 °C, 10 min; (o) 1,10-(azodicarbonyl)dipiperidine (1.2 equiv), n-Bu3P (1.2 equiv), 80 °C, 18 h; (p) NaOH (1 N aq, 1.3 equiv), EtOH, 75 °C, 18 h; (q) Chiral Pak
AD preparative column (10% EtOH/hexanes), faster eluting enantiomer.
Table 2
Table 3
Bioavailability and exposure of compound 18a or 18b after oral administration in
Sprague Dawley rats or Beagle dogs
Assessing the hERG affinity, exposure, and extent of hydrolysis of the zwitterionic
prodrugs 18a, 21–24 in rat and human whole blood/liver
Formulationa
Fb (%)
AUC0–24 h
(lM h)
Compd hERG Ki (
lM)
% Conversion to 18ba
AUC0–24 h
(l
M h)
b
b
Entry
Dosed as parent acid 18b
Whole blood
Liver S9
1
2
3
4
5
6
7
8
0.5% methocel
60% PEG 200
60% PEG 200 (pH 2.5)
Peanut oil
Lyposin II
Na salt in 0.5% methocel
Ca salt in 0.5% methocel
Intra-duodenumc
1
4
1
1
0
1
0
0
0.1
0.5
0.1
0.1
0.03
0.1
0.3
0
Rat
Human Rat Human
Acid-based prodrugs
18a
21
0.08
0.2
99
100
100 38
100 56
3
1
60
66
81
83
56
––
90
95
5.7
3.5
0
22
––
23
0.04
0.2
Piperidine-based prodrugs
24 3.7
93
11
98
99
0.2
Dosed as ethyl ester prodrug 18a
9
10
0.5% Methocel, rats
52
6
5.7
a
After 20 min preincubation (n = 2).
Administered orally in Sprague Dawley rats (n = 2) at 30 mg/kg, 5 mL/kg in 0.5%
0.5% Methocel, dogsd
0.01 (0.03)e
b
a
b
c
methocel for 18a, 21–23 and 20 mg/kg; 5 mL/kg in 0.5% methocel for 24. AUC is
with respect to 18b.
Administered orally in Sprague Dawley rats (n = 2) at 30 mpk, 5 mL/kg.
Unless otherwise noted, AUC and F are with respect to 18b.
Administered intra-duodenum at 20 mpk, 1 mL/kg in 5% dextrose.
Administered orally to Beagle dogs (n = 2) at 3 mpk, 5 mL/kg.
Value in parenthesis is exposure levels of prodrug 18a.
d
e
or absence of NADPH. Indeed, attempts to reduce either the hERG
affinity or CYP3A4 inhibitory activity via the incorporation of a
carboxylic acid has been previously documented in the literature.19
Encouraged by these findings, 18b was selected for further phar-
macokinetic profiling in Sprague Dawley rats. Unfortunately,
when the compound was administered orally at 30 mpk as a 0.5%
on reducing the hERG binding and the CYP3A4 IC50 shift (com-
pounds 13–18a). The only exception was the zwitterionic inhibitor
18b which demonstrated a favorable reduction in hERG affinity
(Ki = 1.07 lM) with no observable CYP3A4 activity in the presence

R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
2433
Cl
O
O
Me
N
Cl
Me
b, c
Me
21
22
R
1 = H, R2
=
=
O
O
O
COOR2
Cl
O
N
O
O
O
a
N
R1
d, e
R1 = H, R2
Me
Cl
OEt
OMe
O
(R1 = BOC, R2 = H)
20
O
COOR2
O
N
f, e
tBu 23
R
1 = H, R2
=
O
N
Cl
O
R1
OMe
O
N
18b (R1 = H, R2 = H)
g
Cl
Me
or
NO2
O
19 (R1 = BOC, R2 = Et)
25
O
COOH
O
O
N
O
O
O
O
O
O
OMe
Me
O
O
O
Me
24
Scheme 2. Reagents and conditions: (a) 19 (1 equiv), NaOH (3 equiv), EtOH, MW 100 °C, 5 min; (b) Cs2CO3 (2 equiv), 2-chloro-N,N-dimethylacetamide (1.2 equiv), DMF,
80 °C; (c) 4 M HCl in dioxane (10 equiv), DCM, rt; (d) 1-chloroethyl ethyl carbonate (1.3 equiv), NaI (0.1 equiv), TEA (2 equiv), acetone, 75 °C, 3 h; (e) ZnBr2 (10 equiv), DCM, rt,
o/n; (f) chloromethyl pivalate (1.1 equiv), DBU (1.1 equiv), ACN:DCM (1:1), rt, 10 h; (g) 18b (1 equiv), 25 (1.2 equiv), DMF, rt, 2 h.
Cl
Cl
O
O
O
O
Cl
Me
Me
Cl
MsO
CN
a, h, c
N
N
O
O
NH
OH
O
N
N
N
N
N
H
BOC
9
OMe
OMe
31
d, e
a
Cl
Cl
O
O
O
O
Cl
Me
Me
Cl
O
O
f, b, c
O
R2
n
N
I
R3
O
N
O
R
N
O
BOC
OEt
N
R
OMe
R1
29
OMe
28
(R1 = BOC, R3 = OMe/OEt)
26
b, c
(R1 = H, R3 = OH)
27
30
b, g, c
(R1 = H, R3 = NHSO2Me)
Scheme 3. Reagents and conditions: (a) (i) RBr, RCl or ROMs (1.3–2.5 equiv), Cs2CO3 or K2CO3 (1.3–4.4 equiv), DMF, 80 °C; or (ii) 1,10-(azodicarbonyl)dipiperidine (1.2 equiv),
n-Bu3P (1.2 equiv), 80 °C, o/n; (b) NaOH (1 N aq, 1.3 equiv), EtOH, 75 °C, o/n; (c) 4 M HCl in dioxane (10 equiv), DCM, rt; (d) 1,2-dibromoethane (20 equiv), 3 M NaOH (2–
5 equiv), Bu4N+HSO4ꢁ, 70 °C, o/n; (e) NaI (1.5 equiv), acetone, reflux; (f) (i) LDA (1.1 equiv), 29 (1.05 equiv), THF, ꢁ78 °C to ꢁ20 °C; (ii) 28 (1 equiv), THF, ꢁ78 °C to rt; (g)
MeSO2NH2 (3 equiv), EDCI (1.5 equiv), DMAP (1.7 equiv), DCM, rt, 3 days; (h) tributyltin azide (3 equiv), dioxane, 150 °C, o/n.

2434
R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
methocel suspension, it was found to have extremely low bioavail-
ability (Table 2, entry 1).
the dog where conversion to the corresponding acid was incom-
plete (entry 10).
In an effort to improve the oral exposure, compound 18b was
dosed in various vehicles, as either the parent acid or its alkali salt,
and at different pH. Representative examples of these studies are
highlighted in Table 2. In summary, all of the formulations at-
tempted offered negligible improvement in terms of oral bioavail-
ability and exposure, including direct administration into the
duodenum (entries 1–8). Speculating that poor cellular permeabil-
ity was a key factor limiting compound 18b’s bioavailability, we
then turned to a prodrug approach as this method was found to
be successful for numerous zwitterionic drugs lacking oral absorp-
tion.21 Pleasingly, when 18b was dosed in the rat as its ethyl ester
prodrug 18a, a dramatic increase in bioavailability and exposure
was realized, with no measurable levels of ester prodrug 18a ob-
served (entry 9). Unfortunately, this finding did not translate into
To ascertain the relevance of these two dichotomous results to
human, the ethyl ester prodrug 18a was incubated in the whole
blood of various species. Significantly different rates of ester
hydrolysis between the species were observed, with the rat being
the most efficient (98%) (rhesus monkey (15%) >dog (2%) ꢂ human
(3%)). These results, taken together with the fact that 18a exhibits a
strong affinity for the hERG channel (Ki = 0.08 lM), necessitated
the design of a more labile prodrug. Specifically, well absorbed pro-
drugs which demonstrated rapid and quantitative conversion in
human whole blood and/or liver were sought.
Table 3 highlights some of the many acid and piperidine-based
prodrugs that were assessed for their ability to hydrolyze in
both human and rat whole blood and liver. Access to the acid-
based prodrugs 21–23 could be achieved from the corresponding
Table 4
Renin buffer and plasma potency, hERG binding, and rat pharmacokinetics of select zwitterionic compounds
Cl
Cl
O
O
O
O
Cl
Me
N
Cl
Me
O
O
Cl
OR
N
N
N
H
N
H
OMe
3
OMe
a
Compd
R
Renin IC50
(nM)
hERG Ki
M)
NADPH-dependent CYP3A4 inhibitonb
Pharmacokinetics in ratsc
po AUC0–24 h Cl (mL/
M h)
(l
ꢁNADPH IC50
M)
+NADPH IC50
M)
IC50
shift
F%
Buffer
0.05
Plasma
3.3
(l
(
l
(
l
min/kg)
62
3
0.2
1.1
>50
>50
1.6
>31.8
72
1
8.6
0.1
COOH
COOH
18b
0.03
0.04
1.1
5.6
>50
ꢀ1
60
49
27a
27b
1.0
0.6
>50
>50
>50
>50
ꢀ1
ꢀ1
2
9
0.2
1.1
Me Me
COOH
COOH
Me Me
Me Me
COOH
COOH
Et Et
0.06
0.02
0.01
0.02
29.6
9.0
44
43
9.7
29
27c
27d
27e
0.4
0.2
0.4
>50
>50
>50
>50
>50
>50
ꢀ1
ꢀ1
ꢀ1
13
22
26
2.1
16
6.1
23.4
5.8
COOH
27f
0.01
0.06
12.4
2.1
0.5
2.3
>50
>50
>50
>50
ꢀ1
ꢀ1
15
3
3.3
1.2
27
23
COOH
27g
Me OMe
O
O
O
S
30
31
0.01
0.03
2.1
5.3
0.5
0.5
>50
>50
>50
>50
ꢀ1
ꢀ1
0
0
0
0
26
46
N
Me
H
N
N
NH
N
a
Average of at least two replicates. See Ref. 12 for assay protocols.
NADPH dependent CYP3A4 inhibition: measures change in the IC50 for CYP3A4 during a 30 min preincubation in the absence and presence of NADPH. IC50 shift P1.5-fold
b
suggests that compound could be a potential TDI. Conversely, IC50 shift <1.5-fold signifies that the compound may not be a TDI. The higher the IC50 shift ratio, the greater the
TDI potential. See Ref. 20 for complete protocol.
c
Administered in Sprague Dawley rats (n = 2): PO = 30 mpk, 5 mL/kg in 0.5% methocel; iv = 3–5 mpk; 1 mL/kg in 60% PEG 200.

R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
2435
intermediate acid 20 via alkylation with a commercially available
chloromethyl alkylating reagent. Conversely, the carbamylation
of 18b with the known (oxodioxolenyl)-methyl carbonate 2522
afforded the piperidine-based prodrug 24 (Scheme 2). Not surpris-
ingly, all of the prodrugs investigated exhibited undesirable
affinities toward the hERG channel with the exception of the piper-
IC50 value of 1.1 nM, hERG Ki of 1.07
l
M and no observed CYP3A4
TDI. While efforts to improve the oral bioavailability of 18b could
be realized with analogues such as 27d–f, where the carboxylic
acid is flanked by larger alkyl groups, this was unfortunately
met with an increase in hERG activity and a reduction in renin
plasma potency. As a result, work on the zwitterionic series was
discontinued.
idine-based prodrug 24 (Ki = 3.7 lM). More importantly, prodrugs
22–24 demonstrated significant conversion to 18b after either
whole blood or liver incubations in both rat and human. Unfortu-
nately, prodrugs 22–24 also failed to afford comparable oral expo-
sures realized with 18a in the rat. As a result, efforts in the prodrug
series were discontinued and new zwitterionic inhibitors with
inherently improved pharmacokinetic properties were sought.
Focusing our efforts around the acid moiety, several lipophilic
acid analogues of varying length, substitution and functionality
were synthesized in hope that the added lipophilicity would trans-
late into compounds with enhanced oral absorption. Once again,
intermediate 9 served as a useful starting point for accessing the
intended zwitterions (Scheme 3). Thus, an alkylation or Mitsunobu
reaction between 9 and an appropriately substituted alkyl halide,
mesylate or alcohol provided access to the ester intermediate 26.
Subsequent ester hydrolysis followed by BOC deprotection pro-
vided access to the final zwitterions 27a–g (Table 4). Alternatively,
a more efficient access to butyric acid analogues could be achieved
from the deprotonation of a commercially available ester 29 and its
subsequent reaction with an alkylating agent as in 30. The acylsul-
fonomide 30 could be easily obtained in three steps from 26 via
hydrolysis of the ester, coupling with methanesulfonamide and
BOC deprotection. Finally, tetrazole 31 could be prepared directly
from the corresponding nitrile by treating it with tributyltin azide
in refluxing dioxane.
References and notes
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In general, all of the acid analogues were found to be highly
potent inhibitors of renin, again confirming the accommodating
nature of the channel situated off the renin S3 pocket (Table 4).
Moreover, none of the acids demonstrated a potential for time
dependent inhibition against CYP3A4, unlike the prototypical com-
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Unfortunately, the gain in bioavailability, exposure and clearance
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philicity and hence off-target activities associated with 3 was
sought. Indeed, a more promising approach involving the trunca-
tion of the northern lipophilic appendage within 3 can offer potent
renin inhibitors with dramatically improved hERG and CYP3A4
profiles. The results of this novel strategy will be disclosed in an
upcoming publication.23
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In summary, we have identified potent zwitterionic-based
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zwitterionic inhibitors of the past. The zwitterion 18b was found
to possess the most interesting in vitro profile, with a plasma renin

2436
R. Aspiotis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2430–2436
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l
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