Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of tertiary alcohol-bearing piperidines

Article abstract of DOI:10.1016/j.bmcl.2011.05.014

The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.

Full text of DOI:10.1016/j.bmcl.2011.05.014

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3976–3981
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Renin inhibitors for the treatment of hypertension: Design and optimization
of a novel series of tertiary alcohol-bearing piperidines
⇑
Austin Chen , Elizabeth Cauchon, Amandine Chefson, Sarah Dolman, Yves Ducharme, Daniel Dubé,
Jean-Pierre Falgueyret, Pierre-André Fournier, Sébastien Gagné, Michel Gallant, Erich Grimm, Yongxin Han,
Robert Houle, Jing-Qi Huang, Gregory Hughes, Hélène Jûteau, Patrick Lacombe, Sophie Lauzon,
Jean-François Lévesque, Susana Liu, Dwight MacDonald, Bruce Mackay, Dan McKay, M. David Percival,
René St-Jacques, Sylvie Toulmond
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2011
Revised 3 May 2011
Accepted 4 May 2011
Available online 14 May 2011
The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by com-
mitting the necessary resources to the development of synthetic sequences and scaffolds that were most
amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one
end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Renin
Inhibitor
Anti-hypertensive
Despite the fact that anti-hypertensive medications with dis-
tinct mechanisms of action have become broadly available in the
past two decades, hypertensive heart disease remains one of the
leading causes of mortality in the developed world.1 As a result,
there continues to be a demand for the discovery of more effica-
cious therapeutic agents that can be used either as monotherapy
or in combination with existing anti-hypertensive agents. In this
regard, one attractive research strategy involves the design and
synthesis of new molecules capable of inhibiting renin, an enzyme
responsible for the rate-limiting conversion of angiotensinogen
into angiotensin I (Fig. 1).2 Although numerous pharmaceutical
companies have embraced this strategy, to date, aliskiren is the
only direct renin inhibitor that has been approved by the FDA for
the treatment of mild to moderate hypertension.3
We have previously reported that piperidines substituted at the
4-position with an N-methyl pyridone (1, Table 1) can serve as
highly potent renin inhibitors.4 During this SAR campaign, it was
observed that the pyridone functionality engages in two key
stabilizing interactions with the renin enzyme: (1) formation of a
H-bond between the pyridone carbonyl and indole NH of Trp45,
(2) formation of a
p-stack between the pyridone ring and phenol
residue of Tyr83. Even though we believed these pyridone-bearing
renin inhibitors possessed all the properties necessary for clinical
⇑
Corresponding author. Tel.: +1 450 218 4017.
E-mail address: austin.chihyu.chen@gmail.com (A. Chen).
Figure 1. The renin–angiotensin–aldosterone system.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.014

A. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3976–3981
3977
Table 1
SAR of select renin compounds: Northern modifications
Ar
R
H
OH
OH
OH
OH
OH
OH
OH
OH
1
7
8
9
10
11
12
13
14
a
Renin buffer IC50 (nM)
12
31
318
990
139
467
54
960
62
479
13
135
9
120
13
97
23
230
a
Renin plasma IC50 (nM)
a
Average of at least two replicates. All compounds were tested as a racemic mixture. See Ref. 8 for assay protocols.
Table 2
Key profiles of compound 15
a,b
Renin IC50 (nM)
Buffer
6.4
Plasma
F (%)
42
17
29
18
36
1.5
5
PK in SD rat (5 mpk I.V.)
0.3 mpk P.O.
3 mpk P.O.
30 mpk P.O.
Cl (mL/min/kg)
T1/2 (h)
Vdss (L/kg)
Efficacy in dTGR (10 mpk P.O.)
Off-target profile
Max. BP ; (mm Hg)
Duration (h)
0
0
4.5
0.9
hERG Ki (
lM)
CYP 3A4 Inhibition IC50
(lM)
a
See Ref. 8 for assay protocols.
Average of at least two replicates.
b
Scheme 1. Synthesis of 6. Reagents and conditions: (a) 0.2 equiv DMAP, 140 °C,
79%; (b) 3 equiv LiCl, 3 equiv ArMgBr, THF, rt, 1 h; (c) chromatographic resolution;
(d) 30 equiv 4 M HCl in dioxane, rt, 1 h or 10 equiv ZnBr2,CH2Cl2.
development, we were intrigued by whether the above favorable
interactions could be maintained or enhanced by another suit-
ably-functionalized aromatic plate.
Since the chemistry developed previously for the synthesis of
compound 1 necessitated the installation of the pyridone handle
at an early stage, an alternative approach that would allow for
end stage structural diversification at the 4-position of the piperi-
dine ring was highly desirable. In this regard, the addition of aryl
organometallics to 4-oxo-piperidine-3-carboxamides5 developed
by Bezençon et al. proved to be the most ideal solution (Scheme
1). Briefly, b-ketoester 24 was first converted to b-ketoamide 4 by
heating with amine 36 in the presence of catalytic quantities of
4-dimethylamino-pyridine. Subsequent LiCl-mediated addition of
an aryl Grignard reagent to amide 4 afforded the corresponding
alcohol 5, albeit as a ꢀ1:1 mixture of diastereomers. Following
the isolation of the desired cis-isomer via repeated column chro-
matography, the final cleavage of the BOC-protecting group could
be readily accomplished either in the presence of a large excess
of 4 M HCl in dioxane or with zinc(II) bromide in CH2Cl2.7
Using compound 7 with its naked benzene as a reference point,
the addition of a methoxy group at the meta-position (i.e., 8) to
Scheme 2. Synthesis of 22. Reagents and conditions: (a) 1.2 equiv AlCl3, CS2, 45 °C,
20 h, 95%; (b) 1 equiv BnNH(CH2)2CN, 2.5 equiv NEt3, THF, 22 °C, 0.5 h, >99%; (c)
1.5 equiv KOtBu, THF, 30 °C, 89%; (d) chiral resolution, AD column, 7:1:1 hexanes/
EtOH/iPrOH; (e) 2.5 equiv LiOH, 5 equiv 30% aq H2O2, DMSO, 45 °C; (f) KOH,
ethanol, 80 °C, 10 h; (g) 0.2 equiv Pd(OH)2 on carbon, 1.2 equiv di-tert-butyl-
dicarbonate, 1 equiv 200 psi H2, ethanol, 22 °C, 2 h, 70% over three steps.

3978
A. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3976–3981
Table 3
SAR of select renin inhibitors: amide modifications
Compound
R1
R2
R3
Renin potencya
Buffer (nM) Plasma (nM)
hERG Ki (
l
M)
CYP 3A4 inhibition
Reversible (% activity)b Time dependent (% loss)c
23
24
25
26
27
28
29
30
31
32
33
Cl
Cl
Cl
F
Cl
Br
F
F
F
F
F
Cl
H
H
H
H
H
H
H
1.2
1.1
1.2
145
61
0.68
1.0
2.2
12
6
9
15
12
16
3
<1
3
67
—
—
18
52
61
—
—
—
—
—
(CH2)3OMe
(CH2)2OMe
H
H
H
(CH2)3OMe
H
(CH2)3OMe
(CH2)3OMe
(CH2)3OMe
110
2.0
1.6
2.1
3.4
6.2
4.4
2.5
2.7
0.24
0.11
0.17
0.07
0.10
0.04
0.26
0.18
1.4
0.91
0.46
1.3
(CH2)3OMe
(CH2)3OMe
(CH2)2CN
CH2SO2Me
1.1
0.85
0.60
1.8
2
8
34
F
(CH2)3OMe
(CH2)3OMe
0.40
1.5
0.90
<1
—
35
F
0.30
2.2
1.4
<1
—
36
37
F
F
H
H
CH2(C@O)NHOMe
CH2(C@O)N(Me)OMe
0.45
1.0
2.2
7.4
8.4
2.1
14
7
14
—
38
39
40
41
42
F
F
F
F
F
H
H
H
H
H
0.06
0.15
0.36
0.03
0.38
0.57
5.2
1.1
8
9
7
8
5
—
—
—
—
—
0.90
0.88
1.9
11
0.42
2.8
0.62
43
F
H
14
190
0.71
5
7
—
44
F
H
0.76
1.5
4.4
—
45
46
47
48
49
50
F
F
F
F
F
F
H
H
H
H
H
H
CH2Ph
0.05
1.5
0.10
0.66
0.04
0.09
1.7
330
14
130
4.8
12
0.25
0.24
0.30
0.16
0.25
0.30
10
5
6
3
5
63
—
—
—
—
—
CH2(2-(OCHF2)Ph)
CH2(3-(OCHF2)Ph)
CH2(4-(OCHF2)Ph)
CH2(3-FPh)
CH2(3,4-F2Ph)
7
51
52
F
F
H
H
0.10
0.08
3.4
1.0
0.34
1.1
3
3
—
—

A. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3976–3981
3979
Table 3 (continued)
Compound
R1
R2
R3
Renin potencya
Buffer (nM) Plasma (nM)
hERG Ki (
l
M)
CYP 3A4 inhibition
Reversible (% activity)b Time dependent (% loss)c
53
54
F
F
H
H
2.5
48
0.36
0.97
20
1
66
—
0.04
0.36
a
Average of at least two replicates. See Ref. 8 for assay protocols.
b
Calculated as a percentage of the difference in the rate of CYP3A4-mediated conversion of testosterone (250
M in DMSO) versus blank DMSO. 50% activity corresponds to a reversible CYP 3A4 inhibition IC50 of 10 M. 10% activity corresponds to a reversible CYP 3A4 inhibition
M.
Calculated as a percentage of the difference in the rate of CYP3A4-mediated conversion of testosterone (250
incubation period with the compound (10 M in DMSO). A 0% loss corresponds to no measurable time-dependent CYP 3A4 inhibition.
lM) to 6-b-hydroxytestosterone in the presence of compound
(10
l
l
IC50 of 2
l
c
lM) to 6-b-hydroxytestosterone before and after 30 min
l
Scheme 3. Synthesis of 58. Reagents and conditions: (a) 1.5 equiv NaH (60% dispersion in oil), DMF, 5 equiv allyl bromide, 80 °C, 5 h, 45%; (b) 0.1 equiv OsCl3, 0.05 equiv
DABCO, 3 equiv K3CO3, 3 equiv K3Fe(CN)6, t-BuOH, water, rt, 15 h, 89%; (c) 10 equiv ZnBr2,CH2Cl2, rt, 1.5 h, 55%.
better engage renin enzyme’s Trp45 was found to be beneficial for
binding. The intrinsic renin potency could be improved further by
simply replacing the methoxy group with either a chlorine (i.e., 9)
Table 4
Key profiles of compounds 49 and 58
or a fluorine (i.e., 10) atom. However, it should be noted that these
Compound
Buffer
49
58
substitutions also afforded compounds that were more shifted in
the presence of human plasma. Regardless, since having a fluorine
at the meta-position appeared to offer the best compromise
between enzyme potency and plasma shift, this element was kept
constant in the following SAR. Further addition of another small,
lipophilic group at either the para- or the other meta-position
improved the renin potency by another three- to seven-fold, with
the 3,4-difluoro substitution pattern (i.e., 13) being optimal. Conse-
quently, compound 13 was resolved and the more potent enantio-
mer (i.e., 15) was profiled (Table 2). Although we were encouraged
by the lack of dependence of bioavailability on dose when 15 was
given orally to SD rats, a common phenomenon that plagued ear-
lier generations of renin inhibitors,9 we were however alarmed
by the compound’s affinity for the hERG channel and by its ability
to inhibit CYP3A4 activity. Furthermore when compound 15 was
given to hypertensive double transgenic rats (dTGR) harboring
both human renin and angiotensinogen,10 we failed to observe
any lowering of blood pressure.
a,b
Renin IC50 (nM)
0.04
4.8
37
0.34
93
9.4
48
15
<0.02
16
<1
0.04
16
2.6
0.4
—
Plasma
F (%)
SD rat (3 mpk P.O., 5 mpk I.V.)
P.O. AUC (
Cl (mL/min/kg)
T1/2 (h)
l
MÃh)
Vdss (L/kg)
Efficacy in dTGR (3 mpk P.O.)
Max. BP ; (mm Hg)
Duration (h)
48
0.25
5
—
0.80
67
hERG Ki (lM)
CYP 3A4 IC50 (nM)
Reversible (% activity)c
Time dependent (% loss)d
—
31
dCalculated as a percentage of the difference in the rate of CYP3A4-mediated con-
version of testosterone (250 M) to 6-b-hydroxy-testosterone before and after
30 min incubation period with the compound (10 M in DMSO). A 0% loss corre-
l
l
sponds to no measurable time-dependent CYP 3A4 inhibition.
a
See Ref. 8 for assay protocols.
Average of at least two replicates.
Calculated as a percentage of the difference in the rate of CYP3A4-mediated
b
c
conversion of testosterone (250
compound (10 M in DMSO) versus blank DMSO. 50% activity corresponds to a
reversible CYP 3A4 inhibition IC50 of 10 M. 10% activity corresponds to a reversible
CYP 3A4 inhibition IC50 of 2 M.
lM) to 6-b-hydroxy-testosterone in the presence of
In order to improve the renin potency further as well as address
the above off-target concerns, we then decided to focus our SAR ef-
fort on the benzyl amide handle. Although the synthetic scheme
l
l
l

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A. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3976–3981
described in Scheme 1 could have been serviceable for this cam-
paign, we again felt it was more prudent to re-design the synthesis
so that the diversification step (i.e., amide coupling) could be post-
poned to the end. In this regard, a scalable route to access the req-
uisite chiral hydroxyl acid 22 was developed (Scheme 2). Briefly,
Friedel–Crafts acylation of 1,2-difluorobenzene (16) with 3-
chloro-propionyl chloride (17) in carbon disulfide afforded ketone
18 in 95% yield. Its subsequent amination with commercially avail-
able 3-(benzylamino)propanenitrile proceeded quantitatively with
triethylamine as base. In the presence of 1.5 equiv of potassium
tert-butoxide, ketone 19 underwent intramolecular cyclization to
afford the desired hydroxyl nitrile as a single diastereomer. Follow-
ing chiral separation on a Chiralpak AD column, the desired enan-
tiomer 20 was hydrolyzed to the corresponding acid 21 by a two
step process: an initial oxidation to the intermediate amide with
lithium peroxide followed by hydrolysis with ethanolic potassium
hydroxide. Finally, a protecting group switch from benzyl amine 21
to tert-butyl carbamate 22 under a hydrogen atmosphere was best
accomplished with Pearlman’s catalyst in the presence of di-tert-
butyl-dicarbonate and triethylamine.
renin potency (i.e., 40 vs 39, 43 vs 42). For analogues capped with
either a benzyl or a pyridyl group, ortho- and para-substitutions
were also not tolerated (i.e., 46 vs 45, 48 vs 45, 53 vs 51). On the
other hand, small substituents at the meta-position (i.e., 49 and
54) were beneficial for renin potency.
Although great strides in terms of renin potency were made and
several low picomolar renin inhibitors were identified, closer exam-
ination would reveal that these gains were often achieved at the ex-
pense of the off-target profile (i.e., hERG binding, CYP3A4 inhibition
or both). Consequently, in order to ascertain whether the judicious
introduction of polarity could free the current series from this
zero-sum quagmire, the tertiary alcohol of compound 4911 was
functionalized as depicted in Scheme 3. Starting from its tert-butyl
carbamate 55, alkylation with allyl bromide was best accomplished
by heating the reactants with sodium hydride in DMF. Subsequent
dihydroxylation of the olefin in 56 using modified Upjohn condi-
tions12 afforded the desired diol 57 as a ꢀ1:1 mixture of diastereo-
mers. Finally, removal of the BOC protecting group with excess
zinc(II) bromide delivered compound 58 uneventfully.7
The key characteristics of compounds 49 and 58 are summa-
rized in Table 4. As expected, the introduction of polarity did im-
With hydroxyl acid 22 in hand, all the amides shown in Table 3
were prepared from the requisite amines with HATU as the cou-
pling agent followed by cleavage of the BOC protecting group. As
expected,4 the best amine identified for the earlier generation
renin inhibitors6 was no longer optimal for our current series.
Indeed, when benzyl amine 3 was switched for N-(2,3-dichloro-
benzyl)cyclopropanamine, a six-fold increase in intrinsic renin po-
tency was observed (i.e., 23 vs 15). However in the absence of a
suitable tail designed to anchor the inhibitor into the renin s3
sub-pocket, compound 23 was also highly shifted by human plas-
ma. Although the plasma shift observed could be slightly decreased
when either 3-methoxypropyl (i.e., 24) or 2-methoxyethyl (i.e., 25)
tail was re-introduced at the meta-position, neither compound
exhibited sufficient renin plasma potency to warrant further profil-
ing. On the other hand, a major potency breakthrough was realized
when we abandoned the benzene ring (i.e., 7 ꢀ 15, 23 ꢀ 25) for an
indole scaffold (i.e., 26 ꢀ 54). Indeed, with only a halogen substitu-
ent at the 4-position of an otherwise unfunctionalized indole ring
(i.e., 26 ꢀ 28), sub-nanomolar renin inhibitors were obtained.
Although it was not possible to differentiate between these ana-
logues on the basis of their respective plasma renin IC50, the 4-flu-
oro derivative 26 appeared to possess the best, albeit still
unacceptable, off-target profile of the three. When compound 26
was docked into the renin active site in silico, molecular modeling
revealed that the renin s3 sub-pocket can be accessed from both
the 1- and 7-positions of the indole ring. Consequently, a 3-meth-
oxylpropyl tail was installed at either of these two positions to as-
sess whether more improvements in potency could be achieved.
While compounds 29 and 30 were both more potent than their
un-alkylated precursor 26 in the enzyme assay, these renin inhib-
itors were however more plasma shifted. Furthermore, these mod-
ifications failed to improve the off-target profile. From 29, the
addition of a second alkyl chain capped by methoxide (i.e., 31),
cyanide (i.e., 32), sulfone (i.e., 33), morpholine (i.e., 34) or imidaz-
ole (35) also failed to deliver any tangible improvement over 26. In
contrast, the replacement of 3-methoxypropane in 29 by an N-
methoxyacetamide (i.e., 36) did lead to a six-fold decrease in bind-
ing affinity to the hERG channel. We have also evaluated the im-
pact of capping compound 26’s indole NH with either a benzyl
(i.e., 45 ꢀ 50) or a heteroaryl methyl (i.e., 38 ꢀ 44, 51 ꢀ 54) resi-
due. Compounds capped with a five-membered heterocycle such
as 1,3-oxazole (i.e., 38) and 3-methyl-1,2,4-oxadiazole (i.e., 41),
or a 6-membered heterocycle such as 4-methyl-3-pyridine (i.e.,
54), were found to be sub-nanomolar renin inhibitors even in the
presence of human plasma. However, further addition of methyl
groups to 5-membered heterocycles proved to be deleterious for
prove the off-target profile to
a more manageable level.
Unfortunately, this was accompanied by a drop in plasma renin po-
tency and more importantly, compound 58 was no longer orally
bioavailable in rats. Consequently, this series was put on hold.
In summary, by committing the necessary resources to the
development of synthetic sequences that were most amenable
for late stage structural diversification, we were able to make a ra-
pid ‘no go’ decision on this series of renin inhibitors. Although
compounds suitable for further development could not be identi-
fied, several members of this series were found to exhibit dose-
independent oral bioavailability in rats. Their use to elucidate the
role of efflux transporters on the poor oral bioavailability shared
by early generation renin inhibitors at low dose will be presented
in a future manuscript.
References and notes
1. http://ucatlas.ucsc.edu/cause.php
2. Zaman, M. A.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug Discovery 2002, 1, 621.
3. Hollenberg, N. K. Nat. Rev. Nephrology 2010, 6, 49.
4. Chen, A.; Campeau, L.-C.; Cauchon, E.; Chefson, A.; Ducharme, Y.; Dubé, D.;
Falgueyret, J.-P.; Fournier, P.-A.; Gagné, S.; Grimm, E.; Han, Y.; Houle, R.; Huang,
J.-Q,; Lacombe, P.; Laliberté, S.; Lévesque, J.-F.; Liu, S.; MacDonald, D.; Mackay,
B.; McKay, D.; Percival, M. D.; Regan, C.; Regan, H.; St-Jacques, R.; Stump, G.;
Soisson, S.; Toulmond, S. Bioorg. Med. Chem. Lett. 2011. doi:10.1016/j.bmcl.
2011.05.013.
ˇ
5. Corminboeuf, O.; Bezençon, O.; Remen, L.; Grisotomi, C.; Richard-Bildstein, S.;
Bur, D.; Prade, L.; Strickner, P.; Hess, P.; Fischli, W.; Steiner, B.; Treiber, A.;
Vaughn, C. Bioorg. Med. Chem. Lett. 2010, 20, 6291.
6. Chen, A.; Bayly, C.; Bezençon, O.; Richard-Bildstein, S.; Dubé, D.; Dubé, L.;
Gagné, S.; Gallant, M.; Gaudreault, M.; Grimm, E.; Houle, R.; Lacombe, P.;
Laliberté, S.; Lévesque, J. F.; Liu, S.; MacDonald, D.; Mackay, B.; Martin, D.;
ˇ
McKay, D.; Powell, D.; Remen, L.; Soisson, S.; Toulmond, S. Bioorg. Med. Chem.
Lett. 2010, 20, 2204.
7. Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C.-G. Synth. Commun. 1989, 19,
3139.
8. Buffer assay: Human recombinant renin (Proteos) at 100 pM was incubated in
the presence or absence of renin inhibitors and 6
DNP-Lys–His–Pro–Phe–His–Leu–Val–Ile–His- -Amp
l
M of Q-FRET substrate 9
in 50 mM MOPS,
D,L
100 mM NaCl, pH 7.4, 0.002% Tween. The reactions take place in a Costar 384
well black plate at 37 °C for 3 h. Fluorescence was measured at times 0 and 3 h
in a SpectraMax Gemini EM reader with excitation and emission filters at 328
and 388 nm, respectively. Plasma assay: Frozen human EDTA-plasma was
rapidly thawed in warm water and centrifuged at 2900 g for 15 min at 40 °C.
The supernatant was collected and recombinant human renin (Proteos) added
at 1 nm nominal concentration. The plasma was transferred to Costar black 384
well plates, renin inhibitors added and the mixture pre-incubated at 37 °C for
10 min. The renin Q-FRET substrate QXL520-Lys–His–Pro–Phe–His–Leu–Val–Ile–
His–Lys-(5-FAM) (Proteos), diluted in 3 M Tris/200 mM EDTA, pH 7.2 was added
to the plasma with final concentrations of 342 mM Tris, 23 mM EDTA and
6.8 lM substrate. The plate was incubated at 37 °C for 1 h and the plate read in
a SpectraMax Gemini EM reader with excitation and emission filters at 490 and
520 nm, respectively, at time 0 and 1 h.

A. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3976–3981
3981
9. In fact, the oral bioavailability of renin inhibitors such as aliskiren increases
nonlinearly with dose. It has been hypothesized that because aliskiren is a good
substrate of endogenous human and rat PGP transporters, this efflux mechanism
would become increasingly saturated at higher doses. Drugs that exhibit this
behavior could have the potential to be victims of drug–drug interactions when
co-dosed with compounds known to inhibit PGP transporters.
10. Hess, P.; Clozel, M.; Clozel, J.-P. J. Appl. Physiol. 1996, 81, 1027.
11. During in silico docking experiment with compound 15, modeling revealed
that the tertiary alcohol residue points out into solvent and does not engage in
any stabilizing interactions with the renin enzyme.
12. Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.