Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin via the S3 pocket

Article abstract of DOI:10.1016/j.bmcl.2011.06.043

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the p

Full text of DOI:10.1016/j.bmcl.2011.06.043

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4836–4843
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin
via the S3 pocket
Jing Yuan a, , Robert D. Simpson a, Wei Zhao a, Colin M. Tice a, Zhenrong Xu a, Salvacion Cacatian a, Lanqi Jia a,
⇑
Patrick T. Flaherty a, Joan Guo a, Alexey Ishchenko a, Zhongren Wu a, Brian M. McKeever a, Boyd B. Scott a,
Yuri Bukhtiyarov a, Jennifer Berbaum a, Reshma Panemangalore a, Ross Bentley b, Christopher P. Doe b,
Richard K. Harrison a, Gerard M. McGeehan a, Suresh B. Singh a, Lawrence W. Dillard a, John J. Baldwin a,
David A. Claremon a
a Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA
b GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented
phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several
parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition
and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive
efficacy in a transgenic rat model of human hypertension.
Received 18 April 2011
Revised 8 June 2011
Accepted 10 June 2011
Available online 17 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Renin inhibitors
Hypertension
Biphenyl
Diphenyl ether
Structure-based design
X-ray crystallography
The renin angiotensin aldosterone system (RAAS) is a central
mechanism by which mammalian blood pressure is controlled.1
The aspartyl protease renin performs the first and rate-limiting
step in the RAAS, cleavage of the decapeptide angiotensin I from
the N-terminus of the glycoprotein angiotensinogen (Fig. 1).
Although renin has long been viewed as a desirable target for anti-
hypertensives, identification of orally bioavailable, low molecular
weight inhibitors proved challenging. Efforts by many research
groups during the 1980s focused on modified peptides, leading to
the identification of potent compounds such as remikiren (1).2,3
However, none of these compounds was ultimately deemed suit-
able for full development.4 Finally in 2007, Novartis brought the
first renin inhibitor, aliskiren (2), to market.5,6
Comparison of the structural features of remikiren (1, Fig. 1) to
the amino acid residues surrounding the cleavage site of the natu-
ral substrate angiotensinogen illustrates the correspondence
between groups occupying the S1, S2 and S3 pockets7 in the
respective structures (PDB code: 3D91). Publication of the first
X-ray structure of human renin (PDB code: 1RNE)8 revealed that
the S1 and S3 pockets form a contiguous superpocket, suggesting
that it might be possible to attach the group filling S3 to the group
occupying S1. Early attempts to reduce this idea to practice led to
compounds with substantially reduced potency.9,10 However,
extensive structure-based design work at Ciba-Geigy, including
deletion of the peptide backbone, led to the identification of
2.11–13 The X-ray crystal structure of 2 bound to renin (PDB code:
2V0Z) confirmed that the methoxyphenyl group occupies S3 and
that the two i-Pr groups occupy S1 and S10.
We recently described the discovery of potent, orally bioavail-
able alkyl amine renin inhibitor 3 (Fig. 1).14 This compound con-
nects the residues filling the S1 and S3 pockets through a
bridging piperidine linker. Inspection of the X-ray structure of 3
bound to renin (PDB code: 3GW5) suggested an alternate inhibitor
design strategy where S1 could be filled by direct attachment of a
suitable group to the ortho-position of the phenyl ring occupying
S3. In this Letter, we describe the successful realization of this de-
sign strategy to afford potent, orally bioavailable renin inhibitors.
Application of Contour™, a proprietary computational struc-
ture-based drug design program, initially identified the phenoxy
group represented in general structure 4 as a candidate to fill the
S1 site, when combined with an appropriate group at R1 (Table 1).
Introduction of the phenoxy group while retaining the
cyclohexylmethyl group at R1 (4a) substantially reduced potency
⇑
Corresponding author.
E-mail address: jyuan@vitaerx.com (J. Yuan).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.043

J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
4837
Figure 1. The N-terminal sequence of angiotensinogen is shown highlighting the amino acids in the P3–P10 positions. The P1, P2 and P3 groups in 1 (remikiren), the P10, P1
and P3 groups in 2 (aliskiren) and the P1 and P3 groups in 3 are indicated.
Table 1
SAR of diphenyl ethers 4
The identification of potent compound 4b provided the first valida-
tion of our design.
As a next step, we surveyed replacement of the substituted eth-
ylene diamine chain in 4 with various cyclic moieties incorporating
basic amines to give compounds of general structure 5 (Table 2.
R3 = aminocycloalkyl, azacycloalkyl, etc.). Presentation of the basic
amine as part of a cyclic structure was intended to retain the key
coulombic interactions with the catalytic aspartates and provide
entropic benefit by removing torsional degrees of freedom present
in the earlier compound 4. From this effort, we identified (3S,1R)-3-
aminocyclopentane-1-carboxylic acid derivative 5a with modest
potency (Table 2). By contrast, the (3R,1R) and (3R,1S)-isomers
5b and 5c were substantially less potent. Modeling of 5a in the re-
nin binding site suggested that additional hydrophobic interac-
tions with the protein could be attained by introduction of a
small lipophilic substituent at the ortho-position of the distal ring
of the diphenyl ether which occupies S1. 2-Methylphenoxy com-
pound 5d proved to be 10ꢀ more potent than 5a. Further examina-
tion of our model indicated that a hydroxyl group at the 4-position
of the cyclopentane ring syn to the 3-amino group would enjoy a
favorable interaction with the Asp32 carboxylate. Thus, 5e exhib-
ited 7ꢀ greater potency than 5d, while the epimer 5f was only
slightly more potent than 5d. Unfortunately, the more potent ana-
logs of general structure 5 also inhibited CYP3A4 with IC50 values
H
N
OH
MeO
N
NHMe
H
R1 R2
O
O
4
a,b,c
Compd
R1
R2
IC50
(nM)
PRAa,b,d (nM)
13
CYP 3A4e
1
(lM)
3c
—
—
H
H
H
H
0.5
596
8.8
420
126
2900
4a
4b
4c
4d
4e
c-hexCH2
i-Bu
t-BuCH2
Me
313
1.1
1.9
1340
Me
Me
a
b
c
See Ref. 14 for assay protocols.
IC50 values are the average of at least two replicates.
Inhibition of 0.3 nM of purified recombinant human renin in buffer was
measured.
d
IC50 in the presence of human plasma.
e
Inhibition of CYP3A4 in human liver microsomes was measured.
61
l
M.
Rat pharmacokinetic parameters were determined for 5e; the
compared to 3, as expected. However, truncation of R1 to i-Bu (4b),
the P1 sidechain in the natural substrate, greatly increased potency.
The closely related t-BuCH2 group (4c) was much less potent. Fur-
ther reducing the size of R1 to Me (4d) reduced potency compared
to 4b. The geminal dimethyl substitution was also unfavorable (4e).
compound showed good oral bioavailability but rapid clearance
(Table 3). The rat liver microsome half life (RLM t1/2) of 5e was
18 min, suggesting that oxidative metabolism might well be the
mechanism of clearance. Introduction of an ortho-fluorine on the
proximal phenyl ring was expected to lock the diphenyl ether into

4838
J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
Table 2
SAR of 3-aminocyclopentane carboxamides 5
OH
MeO
N
R3
Y
H
O
6
5
O
X
3
4
R3
X
Y
IC50
195
(nM)
PRAa,b,d (nM)
CYP 3A4e
(lM)
RLM t1/2 (min)
a,b,c
Compd
5a
H
H
NH2
NH2
NH2
NH2
5b
5c
5d
H
H
H
H
H
1437
>5000
19
2-Me
2-Me
306
32
0.4
0.5
OH
5e
5f
H
2.7
11
18
31
NH2
OH
H
2-Me
2-Me
233
19
1.0
0.4
NH2
OH
5g
3-F
1.2
NH2
a
b
c
See Ref. 14 for assay protocols.
IC50 values are the average of at least two replicates.
Inhibition of 0.3 nM of purified recombinant human renin in buffer was measured.
IC50 in the presence of human plasma.
d
e
Inhibition of CYP3A4 in human liver microsomes was measured.
a favorable conformation and reduce oxidative metabolism; a
modest increase in potency and RLM t1/2 of 31 min were observed
(5g).
phenyl ring of the biphenyl ring system. Thus, 6c (Y = 3-Me) was
more potent than both the unsubstituted biphenyl 6a and the 2-
and 4-methyl isomers 6b and 6d. Another improvement in potency
was obtained with 3-chloro compound 6e. Modeling indicated that
the chlorine interacted favorably with Val30 and Val120 in the S1
pocket. Unfortunately, 6e suffered a greater loss in potency in the
presence of plasma than 6c. However, both 6c and 6e were more
stable in RLM than 5e. Introduction of small lipophilic substituents
at the 3-position of the proximal phenyl ring was predicted to in-
crease potency by locking the biphenyl system into a favorable
conformation for binding to renin; this was borne out with fluoro
analog 6f and chloro analog 6i. Introduction of fluorine at the 4-po-
sition (6g) and particularly the 5-position (6h) reduced potency. As
seen with 6e, chloro analogs 6i–k, while potent when assayed in
buffer, suffered >20ꢀ losses in potency in presence of plasma.
In peptidomimetic renin inhibitors, analogs with aryl rings at P1
are much less potent than compounds with aliphatic groups.15 Fur-
thermore, the majority of the previously described classes of po-
tent, non-peptidic renin inhibitors that bind to the closed form of
renin fill S1 with an aliphatic group;16 however, workers at Sano-
fi-Aventis have recently described inhibitors which deploy a phe-
nyl ring in S1.17 Modeling suggested that replacement of the
diphenyl ether with a biphenyl system would be tolerated while,
potentially, offering superior intrinsic metabolic stability. Unsub-
stituted biphenyl analog 6a demonstrated moderate overall po-
tency (Table 4). Modeling indicated that small lipophilic
substituents could be accomodated at the 3-position of the distal
Table 3
Rat pharmacokinetic parametersa,b
Compd
Oral Cmax (ng/mL)
Oral tmax (h)
Oral AUC(0–t) ng h/mL
Oral t1/2 (h)
iv CL (mL/min.kg)
Vss (L/kg)
F (%)
3
5e
6i
73
185
60
5.6
45
71
3.3
4.3
3.3
0.2
2.7
2.3
3.3
472
728
264
23
186
295
338
nd
33
66
39
50
80
58
53
nd
12
9
39
25
19
83
13
34
8
3.8
4.1
50
15.3
4.9
3.1
7bc
8a
8b
8d
2
14
13
19
111
a
b
c
All compounds were dosed as fumarate salts at 2 mg/kg iv.
All compounds were dosed as fumarate salts at 10 mg/kg po except 7b.
Oral dose 7 mg/kg.

J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
4839
Table 4
SAR of biphenyls 6
OH
NH2
OH
MeO
N
H
O
6
X
5
Y
3
4
a,b,c
Compd
X
Y
IC50
(nM)
PRAa,b,d (nM)
CYP 3A4e
(
lM)
RLM t1/2 (min)
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
H
H
H
37
23
10
20
2.1
1.4
7.1
4700
1.6
1.9
420
126
137
405
79
4.0
0.5
1.6
0.9
0.2
0.8
2-Me
3-Me
4-Me
3-Cl
3-Me
3-Me
3-Me
3-Me
3-Cl
67
73
H
3-F
4-F
5-F
3-Cl
3-F
3-Cl
12
50
35
47
131
0.2
0.5
2.0
102
6j
6k
3-Cl
3.7
a
See Ref. 14 for assay protocols.
IC50 values are the average of at least two replicates.
Inhibition of 0.3 nM of purified recombinant human renin in buffer was measured.
IC50 in the presence of human plasma.
Inhibition of CYP3A4 in human liver microsomes was measured.
b
c
d
e
Many analogs of general structure 6 posessed submicromolar IC50
values against CYP3A4.
the second phenyl ring in the S1 pocket interacting with Tyr75.
Modeling based on 3Q3T predicted that the m-positions of both
the phenyl rings have ample room to allow small substituents to
occupy hydrophobic spaces in the S1 and S3 pockets and provide
improved affinity as observed for 6c, 6e–g and 6i–k.
In rat, 6i demonstrated reduced iv clearance, consistent with its
longer RLM t1/2, but reduced orally bioavailability, compared to 5e
(Table 3). In addition, the IC50 value for 6i in the presence of human
plasma (PRA) was unsatisfactory due to projected inferior efficacy
in vivo. Our subsequent efforts were directed to identify analogs
with improved PRA, reduced CYP3A4 inhibition and increased oral
bioavailability.
An X-ray structure of unsubstituted biphenyl 6a complexed to
renin (PDB code: 3Q3T) confirmed the modeled binding pose
(Fig. 2). Strong electrostatic interactions of the protonated cyclo-
pentylamine with the Asp32 and Asp215 side chain carboxylates
provide a key, anchoring interaction. In addition, the hydroxyl sub-
stituent on the cyclopentane donates a hydrogen bond to the
Asp32 carboxylate. The tertiary alcohol moiety hydrogen bonds
with Ser219, as observed in the crystal structure of 3 bound to re-
nin (PDB code: 3GW5). The ether oxygen at the terminus of the
methoxybutyl chain occupying the S3 subpocket forms a hydrogen
bond with the backbone NH of Tyr14, as seen for the analogous
groups in 2 (PDB code: 2V0Z) and 3 (PDB code: 3GW5). The S3–
S1 superpocket filled by the biphenyl moiety, has the phenyl ring
in the S3 pocket interacting with the positive edge of Phe117 and
In earlier work with related compounds, our general approach
to improving PRA and reducing CYP inhibition was to introduce
additional polar functionality into the molecule.18 Specifically, in
these earlier compounds, removal of the hydroxyl group and
Figure 2. X-ray structure of 6a bound to renin (PDB code: 3Q3T). The molecular surface corresponding to certain amino acid residues of the binding site was not rendered to
provide an unobstructed view of the inhibitor and its interactions.

4840
J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
replacement of the 4-methoxybutyl chain occupying S3sp with an
acylated 2-aminoethoxy chain greatly improved PRA inhibition.
By contrast, in this series, the same modification decreased po-
tency both in buffer and in the PRA (7a vs 6f). On the other hand,
retention of the hydroxyl and replacement of the 4-methoxybutyl
chain with a 3-(methoxycarbonylamino)propyl chain afforded 7b
with improved PRA (Table 5). Replacement of fluorine with chlo-
rine (7c) was well tolerated. 3-(Acetylamino)propyl analogs 7d
and 7e also had good activity in the PRA and offered a modest
reduction in CYP3A4 inhibition. Compound 7b was advanced to
rat PK. Despite its long RLM t1/2, 7b was subject to rapid clearance
in vivo and had low oral bioavailability (Table 3).
to chlorine (8b) and methyl to ethyl (8c) improved renin potency
(Table 6). Combining, these afforded 8d with an excellent in vitro
profile. Interestingly, replacing the ethyl group in 8d with isopro-
pyl (8e) had little effect on renin potency but led to a substantial
increase in CYP3A4 inhibition. Oral bioavailability was demon-
strated for 8a, 8b and 8d, but clearance remained high for all three
compounds (Table 3). Compounds 8a–f also demonstrated excel-
lent selectivity for renin over three other aspartyl proteases: b-
secretase, cathepsin D and cathepsin E (<10% inhibition at 10 lM).
The antihypertensive efficacy of 8d was demonstrated in a dou-
ble transgenic rat (dTGR) model of human hypertension, in which
the animals express both human renin and human angiotensino-
gen (Fig. 3).19,20 Oral administration of 10 mg/kg of 8d led to a sta-
tistically significant reduction in mean arterial blood pressure
(MABP) sustained for more than 12 h. At the nadir, MABP was re-
duced by >20 mm Hg.
Replacement of the piperidine ring in 6 with morpholine offered
an alternative strategy to increase overall polarity. Effecting this
change in 6f gave 8a, with a 3ꢀ reduction in renin potency but a
30ꢀ reduction in CYP3A4 inhibition (Table 6). Changing fluorine
Table 5
SAR of polar side chain analogs 7
OH
R4
R5
N
NH2
H
O
Y
X
R4
R5
IC50
(nM)
PRAa,b,d (nM)
CYP 3A4e
(l
M)
RLM t1/2 (min)
a,b,c
Compd
X
Y
7a
7b
7c
7d
7e
F
F
Cl
F
Cl
Me
Me
Me
Me
Me
H
MeOCONHCH2CH2O–
MeOCONH(CH2)3–
MeOCONH(CH2)3–
MeCONH(CH2)3–
MeCONH(CH2)3–
5.2
1.6
1.1
1.6
2.1
52
0.5
3.8
1.1
5.3
3.5
OH
OH
OH
OH
4.4
2.8
1.7
4.4
567
460
2033
a
b
c
See Ref. 14 for assay protocols.
IC50 values are the average of at least two replicates.
Inhibition of 0.3 nM of purified recombinant human renin in buffer was measured.
IC50 in the presence of human plasma.
d
e
Inhibition of CYP3A4 in human liver microsomes was measured.
Table 6
SAR of morpholine analogs 8
OH
NH2
O
OH
MeO
N
H
O
Y
X
PRAa,b,d (nM)
CYP 3A4e
(lM)
RLM t1/2 (min)
a,b,c
Compd
X
Y
IC50
(nM)
8a
8b
8c
8d
8e
8f
F
Cl
F
Cl
Cl
Cl
Me
Me
Et
Et
i-Pr
MeS
3.8
1.8
2.5
1.1
0.7
2.3
17
11
8.1
4.0
5.2
26
25
18
17
10
0.4
2
99
a
b
c
See Ref. 14 for assay protocols.
IC50 values are the average of at least two replicates.
Inhibition of 0.3 nM of purified recombinant human renin in buffer was measured.
IC50 in the presence of human plasma.
d
e
Inhibition of CYP3A4 in human liver microsomes was measured.

J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
4841
conditions to give intermediate 19, which was further cyclized
and protected to afford morpholine benzyl ether 21.22 The benzyl
group of compound 21 was removed by hydrogenation to afford
alcohol 22, which was oxidized to acid 24 using trichloroisocyanu-
ric acid (23) and TEMPO in excellent yield. It was determined
experimentally that Grignard additions to morpholine ketones
such as 26 occur under chelation control. This dictated that the or-
der of addition of the methoxybutyl group and the biphenyl moiety
be reversed from that used in the synthesis of piperidine interme-
diates 12 and 16. Thus, acid 24 was converted to Weinreb amide 15
and treated with (4-methoxybutyl)magnesium chloride to afford
ketone 26. A variety of substituted biphenyl lithiums (10b) was
added to ketone 16 to give, after removal of the Boc group under
mild conditions, the desired morpholine intermediate 27 as the
major product which was utilized in the synthesis of analogs 8.
The assembly of ureas 4 is shown in Scheme 3. Commercially
available Boc-amino acids 28 were converted to the corresponding
methyl amides 29, which were reduced with Red-Al to afford sec-
ondary amines 30 in reasonable yields. After protecting the sec-
ondary amine with Teoc, the Boc group of compounds 31 was
selectively removed using p-toluenesulfonic acid under vaccum
at 60 °C to give primary amines 32. Amines 32 were then activated
with p-nitrophenyl chloroformate to form their p-nitrophenylcar-
bamates, which were reacted with piperidine 12a (X, Y = H) to af-
ford the urea. Finally, the Teoc group was removed with Et4N+Fꢁ in
acetonitrile to give the desired analogs 4.
The formation of target compounds 5–8 is shown in Scheme 4.
Commercially available stereoisomers of Boc-protected amino es-
ters 34 were hydrolyzed to the carboxylic acids 33b under mild
conditions. The Boc-protected amino acids 33 were then coupled
with piperidines 12 or 16 or morpholines 27 under standard amide
formation conditions, followed by Boc removal, to afford 5–8.23
Scheme 5 shows the synthesis of target compound 7a. Ketone
11b was reduced by NaBH4 to alcohol 35 as a mixture of diastere-
oisomers, which was alkylated to give ester 36. Ester 36 was re-
duced to alcohol 37, which was elaborated to primary amine 38
in three steps. The diastereomers of 38 were separated by prepara-
tive HPLC. Methyl carbamate formation and removal of the Boc
group gave piperidine 39. Coupling the (1S,3R,4S)-isomer of 33b
with 39, followed by deprotection afforded 7a.
Vehicle (n=6)
30
20
10mg/kg po (n=6)
10
0
-10
-20
-30
-40
0
6
12
18
24
Time (hrs)
Figure 3. Effect of 8d on mean arterial blood pressure in dTGR.
The syntheses of piperidines 12 and 16, which comprise the left
hand sides of the target compounds 5, 6 and 7, are shown in
Scheme 1.21 (R)-Boc-nipecotic acid 9 was converted to the corre-
sponding Weinreb amide and treated with various substituted di-
phenyl ether (10a) or biphenyl (10b) lithiums to afford ketone 11.
Addition of (4-methoxybutyl)magnesium chloride to ketone 11
afforded the desired Boc-protected alcohol as the major product
(75–80%). To avoid elimination of the tertiary alcohol, the Boc
group was removed under mild aqueous conditions to afford key
intermediate 12.
Similarly, addition of Grignard reagent 14, which was generated
from protected amine 13, to ketone 11b afforded, after aqueous
work up, aminoalcohol 15 as the major product. The amino group
in 15 was treated with acetic anhydride or methyl chloroformate,
followed by removal of the Boc group under mild conditions, to af-
ford key piperidine intermediates 16. The stereochemistry of the
newly formed carbinol center in both 12 and 16 was initially as-
signed based on the results obtained in analogous reactions re-
ported previously.14 These assignments were subsequently
confirmed by the X-ray structure of derived compound 6a (PDB
code: 3Q3T).
In conclusion, we have described the structure based design of a
topologically novel class of renin inhibitors in which an unprece-
dented phenyl ring filling the S1 site is attached to the phenyl ring
filling S3. The predicted binding mode was confirmed by X-ray
The synthesis of morpholine intermediate 27 is shown in
Scheme 2. Epoxide 17 was opened by amine 18 under basic
Scheme 1. Synthesis of piperidine intermediates. Reagents and conditions: (a) MeNHOMeꢂHCl, EDC; i-Pr2NEt, CH2Cl2, rt, 16 h; (b) 10a, THF, ꢁ20 to ꢁ10 °C, 30 min to 1 h; or
10b, THF, ꢁ78 °C to rt, 16 h; (c) for 11a: MeO(CH2)4MgCl, THF, ꢁ10 °C to ꢁ78 °C to rt, 16 h; for 11b, MeO(CH2)4MgCl, THF, ꢁ78 °C to rt, 16 h; (d) 1:1 2 M aq HCl/MeCN, rt, 16 h;
(e) Mg, THF, reflux, 2.5 h; (f) 11b, THF, ꢁ78 °C to rt, 16 h; (g) for 16a: MeOCOCl, DMAP, Et3N, CH2Cl2; for 16b: Ac2O, DMAP, Et3N, CH2Cl2.

4842
J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
Scheme 2. Synthesis of morpholine intermediates. Reagents and conditions: (a) NaOH, MeOH/H2O, 40 °C, 2 h; (b) NaOH, toluene, H2O, 65 °C, 16 h; (c), (Boc)2O, K2CO3, 3:1
acetone/H2O, 0 °C to rt, 30 min; (d) Pd–C, H2, MeOH, rt; (e) TEMPO, NaBr, NaHCO3, acetone; (f) MeNHOMe, HBTU, HOBt, DIEA, DMF; (g) MeO(CH2)4MgCl, THF, ꢁ20 °C, 10 min;
(h) 10b, THF, toluene, ꢁ20 °C, 10 min; (i) 1:1 2 M aq HCl/MeCN, rt, 16 h.
Scheme 3. Synthesis of ureas 4. Yields are shown for 4a and are representative. Reagents and conditions: (a) MeNH2ꢂHCl, HOBt, HBTU, i-Pr2NEt, DMF, 0 °C to rt, 2 h; (b) Red-
Al, toluene, 0 °C to rt, 16 h; (c) Teoc-OSu, K2CO3, 3:1 acetone/H2O, 0 °C to rt, 1.5 h; (d) TsOHꢂH2O, EtOH, ether, 60–65 °C, 30 min; (e) p-NO2C6H4OCOCl, pyridine, CH2Cl2, rt,
5 min; (f) 12a (X, Y = H), i-Pr2NEt, 1:1 MeCN/CH2Cl2; (g) Et4N+Fꢁ, MeCN, 50 °C, 16 h.
Scheme 4. Synthesis of amides 5–8. For definitions of X, Y, R7 and cyclopentane stereochemistry, see Tables 3–6. Reagents and conditions: (a) 1 N NaOH, 1:1 EtOH/THF; (b)
HOBt, HBTU, i-Pr2NEt, DMF, rt, 5 min; (c) 1:1 2 M aq HCl/MeCN, rt, 16 h.

J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
4843
Scheme 5. Synthesis of 7a. Reagents and conditions: (a) NaBH4, CH3OH, rt, 2 h; (b) BrCH2CO2Et, NaH, THF, 0 °C to reflux, 12 h; (c) NaBH4, CH3CH2OH, rt, 16 h; (d) MsCl, Et3N,
CH2Cl2, 0 °C to rt, 1 h; (e) NaN3, DMF, 80 °C, 5 h; (f) Pd–C, H2, CH3OH, rt, 16 h; (g) preparative HPLC; (h) MeOCOCl, DMAP, Et3N, CH2Cl2; (i) 1:1 2 M aq HCl/MeCN, rt, 16 h; (j)
(1S,3R,4S)-33b, HOBt, HBTU, i-Pr2NEt, DMF, rt, 5 min.
14. Tice, C. M.; Xu, Z.; Yuan, J.; Simpson, R. D.; Cacatian, S. T.; Flaherty, P. T.; Zhao,
crystallography. This effort culminated in the discovery of 8d, a po-
tent, selective and orally bioavailable inhibitor of renin which
effectively lowered blood pressure in an animal model of human
hypertension.
W.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; Scott, B. B.; Bukhtiyarov, Y.;
Berbaum, J.; Mason, J.; Panemangalore, R.; Cappiello, M. G.; Mueller, D.;
Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A.
Bioorg. Med. Chem. Lett. 2009, 19, 3541.
15. Sham, H. L.; Rempel, C. A.; Stein, H.; Cohen, J. J. Chem. Soc., Chem. Commun.
1987, 683.
16. Evolution of diverse classes of renin inhibitors through the years Tice, C. M.;
Singh, S. B. In Aspartic Acid Proteases as Therapeutic Targets; Ghosh, A., Ed.;
Wiley-VCH, 2010; vol. 45, p 297.
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23. Compound 8d gave the following spectral data: 1H NMR (400 MHz, CD3OD) d
7.69–7.66 (m, 1H), 7.30–7.12 (m, 4H), 6.88–6.84 (m, 2H), 6.59 (s, 2H), 4.23–
4.12 (m, 2H), 3.75–3.57 (m, 2H), 3.43–3.33 (m, 1H), 3.27–3.00 (m, 9H), 2.75–
2.54 (m, 3H), 2.23–1.79 (m, 3H), 1.68–1.12 (m, 9H), 0.86–0.75 (m, 1H); MS ESI
+ve ionization, m/z 545, 547 (M+H+).