Design and optimization of renin inhibitors: Orally bioavailable alkyl amines

Article abstract of DOI:10.1016/j.bmcl.2009.04.140

Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC₅₀ of 0.47 nM, caused a sustained reduction in mean arterial bl

Full text of DOI:10.1016/j.bmcl.2009.04.140

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3541–3545
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and optimization of renin inhibitors: Orally bioavailable alkyl amines
a
a
a
a
a
Colin M. Tice a, , Zhenrong Xu , Jing Yuan , Robert D. Simpson , Salvacion T. Cacatian , Patrick T. Flaherty ,
Wei Zhao a, Joan Guo a, Alexey Ishchenko a, Suresh B. Singh a, Zhongren Wu a, Boyd B. Scott a,
Yuri Bukhtiyarov a, Jennifer Berbaum a, Jennifer Mason a, Reshma Panemangalore a,
Maria Grazia Cappiello a, Dominik Müller b, Richard K. Harrison a, Gerard M. McGeehan 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 Charité Berlin, Dept of Pediatric Nephrology, Augustenburger Platz 1, 13353 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin
inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC50 of 0.47 nM, caused a sus-
tained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 March 2009
Revised 27 April 2009
Accepted 30 April 2009
Available online 5 May 2009
Keywords:
Renin
Aspartyl protease
Antihypertensive
Structure based drug design
The renin angiotensin system (RAS, Fig. 1) plays an important
role in the regulation of blood pressure and has been a prominent
target for antihypertensive drugs.1,2 Renin is a highly specific
aspartic protease which catalyzes one step in the RAS, the cleavage
of angiotensinogen which releases the decapeptide angiotensin I
(Ang I). Renin has no other characterized activity and, while
cathepsin D and tonin can also cleave angiotensinogen to Ang I, un-
der normal conditions this activity is not pharmacologically
relevant.3
Renin has long been recognized as a desirable target for antihy-
pertensive therapy. Potent peptidomimetic inhibitors, for example,
remikiren (RO 42-5892, 1, Fig. 2) were discovered during the 1980s
at many pharmaceutical companies.4,5 None of these inhibitors,
which typically had high MW and poor oral bioavailability, were
developed as drugs. However, animal studies demonstrated that
blood pressure lowering could be achieved with a renin inhibitor.6
More recent research has lead to the discovery of several classes
of non-peptidic renin inhibitors.7 Aliskiren (2) is the first marketed
renin inhibitor.8 Piperidine 3 and diaminopyrimidine 4 are repre-
sentative of other chemotypes.9,10 In this Letter we describe the
structure based discovery and initial optimization of a novel class
of potent, low MW, orally bioavailable renin inhibitors.
Starting with a published renin crystal structure (PDB code:
1rne), we applied ContourTM, a computational structure-based de-
sign tool proprietary to Vitae Pharmaceuticals, to design novel li-
gands in the substrate binding site. Our goal was to identify
molecules that contained an amine that would make the key inter-
action with one or both of the catalytic aspartic acids. This would
provide a class of molecules that would have a water solubilizing
charged atom, thus eliminating many of the issues associated with
insoluble chemotypes. Strategically it was decided that optimiza-
tion of the molecules would be limited to the interactions with
sp
the S1, S3 and S3 pockets in order to minimize the molecular
weights of the inhibitors while leaving S2, S4 and the prime side
unoccupied. This approach was supported using Contour’s scoring
algorithm for predicting enzyme binding affinity. After a limited
number of design and synthesis iterations, urea
5 (Fig. 3,
IC50 = 663 nM), initially prepared as a mixture of isomers at the
piperidine and benzyl ether centers, emerged as an attractive
structure for further optimization. Our model of 5 bound to renin
indicated that the preferred isomer would have the (R) stereo-
chemistry at both the piperidine and the benzylic positions. It
placed the terminal primary amine between the two catalytic
aspartates, Asp32 and Asp215, the cyclohexylmethyl group in S1,
the benzyl group in S3 and the methoxypropoxy side chain in
S3sp. The importance of the methoxypropoxy group for potency
* Corresponding author. Tel.: +1 215 461 2042; fax: +1 215 461 2006.
E-mail address: ctice@vitaerx.com (C.M. Tice).
was confirmed by the synthesis of 6 (IC50 = 44 lM).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.140

3542
C. M. Tice et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3541–3545
Figure 1. The renin angiotensin system.
Figure 2. Renin inhibitors.
Our synthesis of the piperidine component of compounds of
afforded secondary amine 16b. Amines 16a and 16b were pro-
tected as their Teoc derivatives and the Boc groups were removed
using p-TsOH12 to give 17a and 17b. Amines 17 were activated as
their p-nitrophenylcarbamate derivatives and reacted with piperi-
dines 12 to form the central urea linkage. Removal of the Teoc pro-
tecting group with Et4NF unmasked the basic amine affording 7.
Analogs 21, with a tertiary alcohol at the benzylic position, were
prepared as shown in Scheme 3. Ketone 9 was treated with 4-
methoxybutylmagnesium chloride to afford 18 which was depro-
tected to afford piperidine 19. The absolute configuration of the
alcohol center in 19 was established by X-ray crystallography of
p-bromobenzenesulfonyl derivative 20. Reaction of 19 with the
p-nitrophenylcarbamate derivative of 17 and deprotection using
the same procedure described for 17?7 in Scheme 2 afforded 21.
Immediately after the discovery of 5, a number of analogs of
general structure 7 were prepared as isomeric mixtures. The activ-
ity of these mixtures in the renin assay (data not shown) suggested
that groups larger than Et at R1 were poorly tolerated. At R2 hydro-
gen and methyl gave better activity than larger alkyl groups. Small
lipophilic aromatic substituents X at the ortho and meta positions
gave promising increases in activity but at the para position only
fluorine was tolerated. The aromatic substituent effects observed
with the isomer mixtures, particularly the improvements in po-
tency observed with small lipophilic substituents at the meta posi-
tion, were consistent with our models and led us to favor meta
substitution when synthesizing additional compounds (Tables 1
and 3).
general structure 7 is shown in Scheme 1. (R)-Boc-nipecotic acid
(8) was converted to its Weinreb amide and reacted with phenyl
Grignard reagents or phenyllithiums to afford ketones 9. Initially
9 (X = H) was reduced with NaBH4 to give a ꢀ1:1 mixture of alco-
hols 10 and 11. In an effort to improve the ratio of 10:11, several
reducing agents were tested and (R)-(+)-2-methyl-CBS-oxazabor-
olidine with catecholborane11 was identified as the most stereose-
lective affording a 13:1 mixture of 10 and 11 when X = H. The
purity of 10 could be further improved by recrystallization. Alkyl-
ation of 10 was effected using large excesses of alkylating agent
and NaH in refluxing THF. Finally, deprotection afforded piperidine
12. The absolute configuration of the benzylic center was estab-
lished by X-ray crystallography of p-bromobenzenesulfonyl deriv-
ative 13.
The mono-protected diamines 17a and 17b were prepared from
Boc protected aminoalcohol 14 via the mesylate 15 (Scheme 2).
Treatment of 15 with NaN3, followed by reduction, afforded pri-
mary amine 16a, while treatment of 15 with methylamine directly
These early promising results prompted us to develop the ster-
eoselective synthesis of piperidines 12 shown in Scheme 1 and pre-
pare target compounds 7 as single isomers. Table 1 shows assay
Figure 3. Prototype alkyl amine renin inhibitors.

C. M. Tice et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3541–3545
3543
Scheme 1. Synthesis of piperidine ether intermediates. Reagents and conditions: (a) MeNHOMeÁHCl, CDI, Et3N, THF; (b) X-Ph-MgX or X-Ph-Li, THF, À70 °C to rt; (c) (R)-CBS
borane, catecholborane, PhMe, À14 °C, 16 h; (d) R1O(CH2)3X (5–10 equiv), NaH (5–10 equiv), THF, reflux; (e) 2 M aq HCl, MeCN, rt; (f) p-BrC6H4SO2Cl, Et3N, CH2Cl2, 0 °C to rt.
Scheme 2. Synthesis of ether analogs. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, À20 °C; (b) NaN3, DMF, 80 °C, 16 h; (c) H2, Pd/C, MeOH; (d) 30% MeNH2 in EtOH, 55 °C,
16 h; (e) TeocOSu, K2CO3, H2O, CH2Cl2; (f) TsOH, EtOH, Et2O, 60 °C; (g) p-NO2C6H4OCOCl, i-Pr2NEt, CH2Cl2, 0 °C; (h) 12, i-Pr2NEt, 1:1 MeCN/CH2Cl2; (i) Et4N+FÀ, MeCN,
100 °C, 10 min.
lwave,
Scheme 3. Synthesis of piperidine alcohol analogs. Reagents and conditions: (a) R1O(CH2)4MgCl, THF, À70 °C; (b) 2 M aq HCl, MeCN; (c) p-BrC6H4SO2Cl, Et3N, CH2Cl2, 0 °C to
rt; (d) 17, Scheme 1 steps g–i.
results for eleven benzyl ethers of general structure 7. Compounds
with ethyl at R1 proved more potent than those with methyl (7b vs
7a; 7j vs 7e; 7k vs 7g) or hydrogen (7i vs 7d). Introduction of a
chloro substituent at the 3-position of the phenyl ring improved
potency over hydrogen (7c vs 7b) and fluorine (7h vs 7j), while
introduction of a chlorine at the ortho position reduced potency
(7k vs 7i). Methyl and hydrogen at R2 were essentially equiactive
(7h vs 7b; 7i vs 7c). Four analogs were assayed against renin in
the presence of human plasma (PRA) resulting in 7–34 fold loss
in potency. Encouragingly, 7h was 35% orally bioavailable in the
rat (Table 2), and had a half life of 5.9 h.
interaction with the backbone carbonyl of Gly217. Our design indi-
cated that the OH of synthetically accessible tertiary alcohols of
general structure 21 (Scheme 3) would donate a hydrogen bond
to the
c oxygen of Ser219, while removing the repulsive interac-
tion of the ether oxygen with Gly217.
The first compound tested was 21a (Table 3), the direct analog
of 7b, which had IC50 = 38 nM. In the tertiary alcohol series R1 = Me
and H were more potent than R1 = Et (21b, 21c vs 21a; 21e vs 21d)
and a further increase in potency was obtained with R2 = Me (21d
vs 21b). Introduction of chlorine at the ortho position of the ben-
zene ring maintained potency (21f) while fluorine gave a slight in-
crease in potency (21g). A broader range of substituents was
explored at the meta position (21h–p) from which the chloro and
Our model of 7 bound to renin revealed that the benzyl ether
oxygen, introduced for reasons of synthetic ease, had a repulsive

3544
C. M. Tice et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3541–3545
Table 1
Table 3
SAR of ether series
SAR of tertiary alcohol series
a,b
a,b
Compd
R1
X
R2
IC50 (nM)
PRAb,c (nM)
190
Compd
R1
X
R2
IC50 (nM)
PRAb,c (nM)
7a
7b
7c
7d
7e
7f
7g
7h
7i
Me
Et
Et
H
H
H
H
H
308
55
5.5
764
58
39
609
40
21a
21b
21c
21d
21e
21f
21g
21h
21i
Et
Me
H
Me
Et
H
H
3-Cl
H
H
2-Cl
2-F
3-Me
3-Et
H
H
38
21
21
7
16
7
4
2.5
9
490
165
315
64
162
151
61
67
285
88
3-Cl
3-Cl
3-F
2-F-3-Cl
2,3-DiCl
H
3-Cl
3-F
2,3-DiCl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
369
447
84
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4
11
125
7j
7k
21j
21k
21l
3-MeO
3-F
3-Cl
13
3
Et
47
13
12
86
0.47
0.13
37
7
a
See Ref. 13 for assay protocol.
Average of at least two replicates.
See Ref. 14 for assay protocol.
21m
21n
21o
21p
21q
21r
21s
21t
21u
21v
2
3-Br
b
c
3-CN
3-CF3
3-CF3O
3-Cl
389
69
6
154
1400
20
27
67
3-Cl
CH2CF3
Me
Me
Me
Me
46
0.14
0.10
3.5
0.9
0.5
2,3-DiF
2-F-3-Cl
2-F-5-Me
3-F-5-Cl
bromo analogs (21l and 21m) stand out as the most promising,
particularly because they retain good activity when assayed in
the presence of human plasma. Introduction of an ethyl group at
R2 (21q vs 21l) somewhat reduced potency while the larger, elec-
tron withdrawing 2,2,2-trifluoroethyl (21r) had an even more sub-
stantial deleterious effect. Selected examples of disubstituted
analogs are shown. The 2,3-difluoro (21s), 2-fluoro-3-chloro(21t)
and 2-fluoro-5-chloro (21v) analogs all had subnanomolar intrinsic
potency but were less potent in the presence of human plasma
than 21l and 21m. The potencies of 21l, 21m, 21s and 21t are equal
or superior to aliskiren (2)8 against renin in buffer but weaker in
the presence of plasma.
Rat PK parameters were determined for six analogs in the ter-
tiary alcohols series (Table 2). Oral bioavailability ranged from
5.5% to 48.3%, AUC values were large and t1/2, where they could
be calculated, were in excess of 5 h. However, the compounds
were all rapidly cleared. Based on its good potency in the pres-
ence of plasma, superior AUC, relatively low clearance and
acceptable oral bioavailability, 21l was selected for advanced
evaluation. Notably, 21l was 10Âmore orally bioavailable in rat
than aliskiren (2).15
28
0.6
a
See Ref. 13 for assay protocol.
Average of at least two replicates.
See Ref. 14 for assay protocol.
b
c
dog and monkey, the apparent terminal half lives (t1/2) following
oral dosing of 21l were both ꢀ16 h.
The animal model used to evaluate the antihypertensive effi-
cacy of 21l was a double transgenic rat (dTGR).16,17 These rats con-
tain copies of both the human angiotensinogen and human renin
genes. They produce high levels of Ang II which leads to a steady
increase in blood pressure, and also generates significant end organ
damage, over the life of the rats.
Compound 21l was tested in a telemetered dTGR cohort (n = 4)
in a repeat dose study. On the first day of the study, animals were
treated with vehicle and BP was monitored over the initial 24 h. On
subsequent days, animals were given 21l by oral gavage (60 mg/
kg). Data in Figure 4 show the BP changes for the first three days
of the study. Vehicle produced no effect and the BP reflected the
diurnal changes over the first 24 h. Dosing with 21l at days 2
(24–48 h) and 3 (48–72 h) produced significant BP lowering. The
pharmacodynamic effect was reproducible and the BP returned
to baseline within 24 h post dose.
Finally, an X-ray structure of 21l bound to renin was deter-
mined at 2 Å resolution (Fig. 5, PDB code: 3gw5). The X-ray struc-
ture was in very close agreement with the model of 21l in the
protein generated using ContourTM.
In conclusion, we have described the structure-based discovery
of a novel series of potent, selective, non-peptidic, low MW renin
The solubility of the fumarate salt of 21l in water was shown to
be >1 mg/mL. The compound showed >1000Â selectivity over the
aspartic proteases pepsin, b-secretase, cathepsin D and cathepsin
E. The IC50 of 21l against the HERG channel in a patch clamp assay
was >30 lM. PK parameters of 21l were determined in dog and
cynomolgus monkey (Table 4). As in rat, the compound was ab-
sorbed rapidly and reached peak plasma concentrations in approx-
imately 1–3 h. The oral bioavailability in monkey was modest
(17%) and similar to that observed in rat. However, in dog it was
significantly higher (38%). The lower oral bioavailability in rat
was due, at least in part, to a combination of high clearance and
incomplete absorption from the gastrointestinal tract. In both
Table 2
Rat pharmacokinetic parametersa,b
Compd
Cmax (ng/mL)
Tmax (h)
AUC(0-t) (ng h/mL)
AUC(inf) (ng h/mL)
T1/2 (h)
IV CL (mL/min kg)
Vss (L/kg)
F (%)
7h
91
28
101
135
83
73
28
4
3.0
2.3
2.0
3.0
2.7
3.3
4.3
0.1
832
221
547
745
433
472
226
21
882
192
689
833
510
530
254
31
5.9
5.1
nd
8.7
9.6
ndb
8.0
13.5
59
46
66
79
59
33
30
55
22
56
nd
55
nd
nd
16
62
35.8
7.5
21b
21d
21e
21k
21l
21t
2
33.6
48.3
21.1
12.9
5.5
1.2
a
Compounds were administered as fumarate salts. PO dose 10 mg/kg. IV dose 2 mg/kg.
nd = not determined.
b

C. M. Tice et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3541–3545
3545
References and notes
1. Zaman, M. A.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug Discovery 2002, 1, 621.
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3. Naseem, R. H.; Hedegard, W.; Henry, T. D.; Lessard, J.; Sutter, K.; Katz, S. A. Basic
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7. Tice, C. M. Ann. Reports Med. Chem. 2006, 155.
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S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G. Chem. Biol. 2000, 7, 493.
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Gruninger, F.; Guenzi, A.; Guller, T.; Hartung, R.; Hirth, G.; Jenny, C.; Kansy, M.;
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Muller, M.; Montavon, F.; Oefner, C.; Qiu, C.; Reichel, A.; Sanwald-Ducray, P.;
Scalone, M.; Schleimer, M.; Schmid, R.; Stadler, H.; Treiber, A.; Valdenaire, O.;
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Zell, R. Il Farmaco 2001, 56, 21.
10. Powell, N. A.; Ciske, F. L.; Cai, C.; Holsworth, D. D.; Mennen, K.; Van Huis, C. A.;
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Bioorg. Med. Chem. 2007, 15, 5912.
11. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925.
12. Rosowsky, A.; Wright, J. E. J. Org. Chem. 1983, 48, 1539.
13. The activity of renin inhibitors in vitro was measured using the following test
protocol: All reactions were carried out in
microtiter plate. A 4
L aliquot of 400 M renin substrate (DABCYL-
His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS) in 192 L assay buffer (50 mM
BES, 150 mM NaCl, 0.25 mg/mL bovine serum albumin, pH 7.0) was added to
L of test compound in DMSO at various concentrations ranging from 10
to 1 nM final concentrations. Next, 100 L of trypsin-activated recombinant
human renin (final enzyme concentration of 0.2–2 nM) in assay buffer was
added, and the solution was mixed by pipetting. The increase in fluorescence at
495 nm (excitation at 340 nm) was measured for 60–360 min at rt using a
Perkin–Elmer Fusion microplate reader. The slope of a linear portion of the plot
of fluorescence increase as a function of time was then determined, and the
rate was used to calculate % inhibition in relation to uninhibited control. The %
inhibition values were plotted as a function of inhibitor concentration, and the
IC50 was determined from a fit of this data to a four parameter equation. The
IC50 is defined as the concentration of a particular inhibitor that reduces the
a
flat bottom white opaque
l
l
c
-Abu-Ile-
l
4
l
lM
l
Figure 4. Effect of 21l on blood pressure in dTGR. Vehicle dosed at t = 0 h. 21l
(60 mg/kg PO) dosed at t = 24 h and t = 48 h.
formation of product by 50% relative to
a control sample containing no
inhibitor. (Wang G. T. et al. Anal. Biochem. 1993, 210, 351; Nakamura, N. et al. J.
Biochem. (Tokyo) 1991, 109, 741; Murakami, K. et al. Anal Biochem. 1981, 110,
232).
14. The activity of renin inhibitors in vitro in human plasma was measured by the
decrease in plasma renin activity (PRA) levels observed in the presence of the
compounds. Incubation mixtures contained in the final volume of 250 lL
95.5 mM N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, pH 7.0, 8 mM
EDTA, 0.1 mM neomycin sulfate, 1 mg/ml sodium azide, 1 mM
phenylmethanesulfonyl fluoride, 2% DMSO and 87.3% of pooled mixed-
gender human plasma stabilized with EDTA. For plasma batches with low
PRA (less than 1 ng/ml/hr) ꢀ2 pM of recombinant human renin was added to
achieve PRA of 3–4 ng/ml/h. The cleavage of endogenous angiotensinogen in
plasma was carried out at 37 °C for 90 min and the product angiotensin I was
measured by competitive radioimmunoassay using DiaSorin PRA kit.
Uninhibited incubations containing 2% DMSO and fully inhibited controls
with 2 lM of isovaleryl-Phe-Nle-Sta-Ala-Sta-OH were used to derive the %
inhibition for each concentration of inhibitors. The % inhibition values were
plotted as a function of inhibitor concentration, and the IC50 was determined
from a fit of this data to a four parameter equation. The IC50 is defined as the
concentration of a particular inhibitor that reduces the formation of product by
50% relative to a control sample containing no inhibitor.
Figure 5. X-ray structure of 21l bound to renin.
inhibitors. The ability to generate potent inhibitors by occupying
only three specificity pockets in the enzyme active site using an
amine interaction with the aspartates has validated our initial de-
sign hypothesis. Moreover, the prototype compound 21l was shown
to be orally bioavailable in three species and caused reproducible
lowering of blood pressure in a transgenic animal model of
hypertension.
15. The oral bioavailability of aliskiren (2) in rat, determined by bioassay, has been
reported to be 2.4%: Wood, J. M.; Schnell, C. R.; Cumin, F.; Menard, J.; Webb, R.
L. J. Hypertens 2005, 23, 417.
16. Luft, F. C.; Mervaala, E.; Muller, D. N.; Gross, V.; Schmidt, F.; Park, J. K.; Schmitz,
C.; Lippoldt, A.; Breu, V.; Dechend, R.; Dragun, D.; Schneider, W.; Ganten, D.;
Haller, H. Hypertension 1999, 33, 212.
17. Mervaala, E.; Muller, D. N.; Schmidt, F.; Park, J.-K.; Gross, V.; Bader, M.; Breu, V.;
Ganten, D.; Haller, H.; Luft, F. C. Hypertension 2000, 35, 587.