Piperidine renin inhibitors: from leads to drug candidates

Article abstract of DOI:10.1016/S0014-827X(01)01004-7

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement

Full text of DOI:10.1016/S0014-827X(01)01004-7

www.elsevier.nl/locate/farmac
Il Farmaco 56 (2001) 21–27
Piperidine renin inhibitors: from leads to drug candidates
H.P. Ma¨rki a,*, A. Binggeli a, B. Bittner a, V. Bohner-Lang a, V. Breu a, D. Bur a,
Ph. Coassolo a, J.P. Clozel a,1, A. D’Arcy a, H. Doebeli a, W. Fischli a,1, Ch. Funk a,
J. Foricher a, T. Giller a,2, F. Gru¨ninger a, A. Guenzi a, R. Gu¨ller a,3, T. Hartung a,
G. Hirth a, Ch. Jenny a, M. Kansy a, U. Klinkhammer a, T. Lave a, B. Lohri a,
F.C. Luft b, E.M. Mervaala b, D.N. Mu¨ller b, M. Mu¨ller a, F. Montavon a,
Ch. Oefner a, C. Qiu a,4, A. Reichel a, P. Sanwald-Ducray a, M. Scalone a,
M. Schleimer a, R. Schmid a, H. Stadler a, A. Treiber a,1, O. Valdenaire a,2, E. Vieira a,
P. Waldmeier a, R. Wiegand-Chou a, M. Wilhelm a, W. Wostl a, M. Zell a, R. Zell a
a Pharma Research, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
b Franz Volhard Clinic, Medical Faculty of the Charite´, Berlin, Germany
Received in revised form 30 November 2000
Abstract
Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of
the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on
improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two
candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-de-
pleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In
addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data
suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the
disease status. © 2001 Elsevier Science S.A. All rights reserved.
Keywords: Renin; Renin-inhibitor; Aspartic proteinase
1. Introduction
cation in various pathological states has been demon-
strated by the efficiency of blockers of this system in
conditions such as hypertension [2], heart failure [3] and
chronic renal failure [4]. The RAS consists of a two-
step cascade: the aspartic proteinase renin cleaves the
peptide bond between Leu10 and Val11 in angiotensino-
gen to form angiotensin (Ang) I. Then, the angiotensin-
converting enzyme (ACE) generates the biologically
active vasopressor octapeptide hormone angiotensin
(Ang) II by removal of the two C-terminal amino acids.
Renin inhibition results in a total blockage of the RAS,
since the cleavage of angiotensinogen by renin repre-
sents its rate-limiting step and is highly specific. ACE,
however, can be bypassed by the serine proteinase
chymase [5] and degrades other pharmacologically ac-
tive peptides such as bradykinin: In certain tissues, e.g.
human heart, chymase has even been shown to be the
The renin–angiotensin system (RAS) is widely ac-
cepted as a key regulator of cardiovascular and renal
function and plays a major role in water and salt
homeostasis and blood pressure control [1,2]. Its impli-
* Corresponding author.
E-mail address: hans p.maerki@roche.com (H.P. Ma¨rki).
–
1 Current address: Actelion Ltd, Gewerbestraße 16, CH-4123
Allschwil, Switzerland.
2 Current address: Axovan Ltd, Gewerbestraße 16, CH-4123
Allschwil, Switzerland.
3 Current address: Chemspeed Ltd, Rheinstraße 32, CH-4302
Augst, Switzerland.
4 Current address: Shanghai Institute of Materia Medica, Shanghai
200031, People’s Republic of China.
0014-827X/01/$ - see front matter © 2001 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01004-7

22
H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
2. Design and synthesis
major Ang II-forming enzyme [6]. Ang II is known to
act on two receptor subtypes: AT1 and AT2. With the
recently discovered novel systems Ang 1–7 [7] and
Ang IV [8] and their specific receptors AT3 and AT4,
the RAS becomes even more complex. Chymase is not
inhibited by ACE inhibitors and the available AT re-
ceptor antagonists only block receptors of the subtype
AT1. Thus, renin inhibition provides the most specific
and complete inhibition of the RAS and displays anti-
hypertensive effects comparable to those seen with
ACE inhibitors and Ang II receptor antagonists [9–11],
but free of side effects due to insufficient specificity.
Several lines of experimental evidence suggest an im-
proved efficacy of renin inhibitors in the tissual systems
of the heart [5,6] and kidney [4,12–14], indicating the
potential for improved prevention and treatment of end
organ damage [15]. A significant number of pepti-
domimetic inhibitors of human renin designed as stable
transition state analogues of the scissile amide bond in
human angiotensinogen have been developed up to
clinical phase II [16–18]. Despite the established clinical
efficacy for several of them, almost all development
compounds were abandoned for reasons of limited oral
bioavailability, rapid biliary elimination and/or too
high cost of goods [19]. Non-peptidomimetic com-
pounds of the piperidine type represent an entirely
novel class of renin inhibitors [20,21] potentially free of
the drawbacks seen with peptidomimetic compounds so
far. The first nanomolar compounds obtained in this
series, however, proved to be highly lipophilic [20].
Recent compounds with improved physicochemical
properties [21] show potent and long-lasting blood pres-
sure lowering effects in conscious sodium-depleted mar-
moset monkeys and thus serve as useful leads for the
development of drug candidates.
Fig. 1 shows a schematic representation of the bind-
ing mode of a sub-nanomolar piperidine human renin
inhibitor in the active site of the enzyme [20]. Most
more-hydrophilic structural modifications in the core of
these inhibitors have dramatically reduced their in-
hibitory potency [21]. Thus, the attachment of suitable
hydrophilic extensions pointing either towards bulk
water (arrows in Fig. 1) or into a mixed polar hydro-
phobic and human renin specific non-substrate S3 sub-
pocket (Ss3p; dashed arrow in Fig. 1) became the favored
approach for the modulation of their physicochemical
properties. X-ray data of renin inhibitors bearing sub-
stituents pointing into this sub-pocket have recently
been described [22,23]. Scheme 1 shows the synthesis of
compound 14 bearing an equatorial 3-methoxy-2-hy-
droxy-propoxy moiety attached to the position 5 of the
piperidine ring together with optimized substituents in
positions 3 and 4. The synthetic scheme is prototypic
for piperidine renin inhibitors with analogous exten-
sions; compare Refs. [20,21,24].
It has been found that the aromatic ring B (Fig. 1) is
the only part in the core of the piperidine renin in-
hibitors that allows hydrophilic modifications [21].
Thus, 3,4-disubstituted piperidine compounds bearing a
tetrahydroquinoline-methoxy substituent in position 3
have shown good inhibitory potency against human
renin and a reduced lipophilicity [21].
Suitably designed tetrahydroquinoline N-substituents
can fit into the non-substrate S3 sub-pocket. Scheme 2
describes the synthesis of the 3,4-disubstituted pipe-
ridine compound 23 bearing an acetylaminoethyl sub-
stituent attached to the tetrahydroquinoline N-function
prototypic for a series of analogous compounds; com-
pare Refs. [20,21,26].
3. Biological results and discussion
There is a high degree of freedom for structural
variations at the 5 position of the piperidine ring (equa-
torial substitution, see Table 1). No substantial differ-
ences can be seen for all compounds shown with respect
to their inhibitory potency against purified recombinant
human renin in buffer and an IC50 range between 2 and
20 nM with respect to their inhibitory potency against
human renin in plasma. The series covers compounds
bearing hydroxy- and alkoxy-substituted alkoxy- and
alkoxy-methyl groups and a compound with an imida-
zolylmethyl function at position 5. These compounds
represent a group of rather hydrophilic piperidine ana-
logues suitable for a more profound characterization in
pharmacokinetic and pharmacodynamic models. Com-
pound 14 (with a 3-methoxy-2-hydroxy-propoxy moiety
at position 5 of the piperidine ring and having the
Fig. 1. Design of potential hydrophilic extensions to piperidine renin
inhibitors (arrows); positions of binding pockets S as seen in X-ray
structures with peptidomimetic inhibitors are indicated; Ss3p refers to a
non-substrate sub-pocket accessible from the S3 pocket [22,23].

H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
23
Scheme 1. Synthesis of 14, prototypic for piperidine renin inhibitors with hydrophilic extensions at position 5; compare Refs. [20,21,24]. Reagents
and conditions: (a) Ph3P+MeCl−, tert-BuOK, THF, room temperature (r.t.), 2 h, 90%. (b) i. R-(+)-1-Phenyl-ethylamine, H2CO (aq.), HCl (aq.),
dioxane, 40°C, 4 h; 74°C, 16 h; ii. H2SO4 (aq.)/dioxane, 100°C, 7 h, 58%. (c) i. HBr (aq. 48%), Br2, dioxane/water, 2.5 h, 3–5°C; ii. NaOH (aq.),
2.5 h, 3–5°C; iii. Cryst. from MeOH with Et3N, 47%. (d) i. PhLi, tert-butyl-methyl ether, −15°C, 90 min; ii. Cryst. from MeOH, 91%. (e) i. NaH,
DMF, r.t.; ii. (R)-(−)-2,2-Dimethyl-4-(hydroxymethly)-1,3-dioxolane p-toluenesulfonate, r.t., 2 h, 84%. (f) i. Borane–THF, DME, r.t., 5.5 h; ii.
Sodium percarbonate (aq.), 50–55°C, 17 h; 74%. (g) H2, Pd/C, MeOH, r.t., 23 h, quant. (h) Di-tert-butyldicarbonate, dioxane/water, sodium
hydrogencarbonate, r.t., 1 h, 85%. (i) 1-(3-Chloro-propoxymethyl)-2-methoxy-benzene [20], potassium carbonate, DMF, 120°C, 21 h, quant. (j)
3-Chloromethyl-1-methoxy-naphthalene (prepared from (4-methoxy-naphthalen-2-yl)-methanol [25] and methanesulfonyl chloride, triethylamine
at r.t.) NaH, DMF, r.t., 1.5 h, 95%. (k) HCl/MeOH (2 N), MeOH, r.t., 1 h, quant. (l) Di-tert-butyldicarbonate, dioxane/water, sodium
hydrogencarbonate, r.t., 1 h, 87%. (m) Toluene-4-sulfochloride (5 equiv.), pyridine, r.t., 15 min, 72%. (n) NaOH (5 N, aq.), DMSO, r.t., 1 h, 98%.
(o) NaOMe, MeOH, DMF, r.t., 9 h, 96%. (p) HCl/MeOH (2 N), MeOH, r.t., 5 h, 97%.
human renin gene [28,29] (Fig. 3), as well as pharma-
cokinetic properties (plasma concentrations after oral
administration to normal rats). The data obtained in
the marmoset monkey model compare well with those
reported for other potent orally active renin inhibitors
[17,18,22,30–32]. In addition, compound 14 was able to
normalize blood pressure and coronary resistance and
prevent cardiac hypertrophy and albuminuria in double
transgenic rats harboring both the human angiotensino-
following physicochemical characteristics: pKa=6.4,
log P=5.7, log D(pH 7.4)=5.6, aqueous solubility as
amorphous hydrochloride of \1% and aqueous solu-
bility at pH 6.6 of 3 mg/ml) clearly showed the most
promising set of data within this compound series. This
data set comprised pharmacodynamic blood pressure
lowering effects in conscious sodium-depleted mar-
moset monkeys (Fig. 2) and in double transgenic rats
harboring both the human angiotensinogen and the

24
H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
Scheme 2. Synthesis of 23, prototypic for piperidine renin inhibitors with hydrophilic extensions pointing into the Ss3p pocket; compare Refs.
[20,21,26]. Reagents and conditions: (a) i. BH3xTHF (1 M), THF, 1 h, r.t.; ii. NaOH (aq.), H2O2 (aq.), 45°C, 3 h, 50% as crystalline pure
diastereomer. (b) H2/Pd/C, MeOH, r.t., 15 h. (c) Di-tert-butyldicarbonate, Et3N, MeOH, −10 to 0°C, 3 h, 96% (two steps), 98.8 to 100% e.e. (d)
1-(3-Chloro-propoxymethyl)-2-methoxy-benzene [20], potassium carbonate, DMF, 66 h, 120°C, 80%. (e) HBr, AcOH, 1 h, 75°C, 97%. (f) NaH,
DMF, 24 h, r.t., 94%. (g) NaBH4, NiCl2, MeOH, 1 h, 0°C, 1 h, r.t., 91%. (h) Na2CO3, MeCN, KI, 16 h, reflux, 90%. (i) ZnBr2, dichloroethane,
2 h, 50°C, 71%.
acetylaminoethyl substituent is the only compound in
the whole piperidine series with sub-nanomolar potency
in the plasma assay (Table 2). This, together with its
physicochemical characteristics (pKa=8.4 and B2;
log P=4.0, log D(pH 7.4)=3.0, aqueous solubility in
presence of two equivalents of hydrochloric acid of
\1% and aqueous solubility at pH 6.6 of 124 mg/ml),
makes it the most promising compound out of this
series. The pharmacodynamic blood pressure lowering
effects in conscious sodium-depleted marmoset mon-
gen and the human renin gene when given at a dose of
30 mg/(kg day) over a period of 4 weeks [29]. In these
rats, a triple therapy with hydralazine at a dose of
80 mg/l, reserpine at a dose of 5 mg/l, and hy-
drochlorothiazide at a dose of 25 mg/l in the drinking
water was equally effective with respect to lowering of
blood pressure, but displayed only marginal effects on
albuminuria. In consecutive studies, it could be demon-
strated that Ang II-mediated inflammatory responses
via NFkB activation play a key role in this model [33].
Thus, renin inhibitors are able to prevent Ang II-in-
duced end-organ damage, pro-inflammatory responses
and cellular growth, effects that are largely independent
of blood pressure.
Table 1
IC50 values (against purified recombinant human renina and human
plasma reninb) of piperidine renin inhibitors with hydrophilic exten-
sions at position 5
Compounds with tetrahydroquinoline nitrogen sub-
stituents, of a length of four to five atoms bearing at
least one non-basic H-bond acceptor function, show a
substantially improved inhibitory potency against hu-
man renin in buffer in comparison with the non-substi-
tuted analogue 29 (Table 2). X-ray data obtained with
compound 23 confirm that the acetylaminoethyl sub-
stituent binds into the S3 sub-pocket (data not shown).
The hydroxyethyl-substituted compound 30 cannot en-
tirely fill the pocket and, therefore, does not show a
potency improvement; an aminopropyl substituent
(compound 35) is not accepted in the pocket, probably
due to its charged amino function, and the acetyl-
aminopropyl-substituted compound 36 shows a dra-
matically reduced inhibitory potency, due to the too
long acetylaminopropyl chain. Compound 23 with the
a For assay conditions see Ref. [20]. The IC50 values depicted are
mean values of two to five independent determinations.
b For assay conditions see Ref. [27]. The IC50 values depicted are
mean values of two or three independent determinations.

H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
25
Fig. 2. Blood pressure lowering effects obtained with compound 14 in conscious sodium-depleted marmoset monkeys in comparison with the ACE
inhibitor Cilazapril.
Fig. 3. Blood pressure lowering effects obtained with compound 14 in double transgenic rats harboring both the human angiotensinogen and the
human renin gene.

26
H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
Table 2
[5] H. Urata, B. Healy, R.W. Steweart, F.M. Bumpus, A. Husain,
Angiotensin-forming pathways in normal and failing human
hearts, Circ. Res. 66 (1990) 883.
[6] A. Wolny, J.P. Clozel, J. Rein, P. Mory, P. Vogt, M. Turino, W.
Kiowski, W. Fischli, Functional and biochemical analysis of
angiotensin II-forming pathways in the human heart, Circ. Res.
80 (1997) 219–227.
IC50 values (against purified recombinant human renina and human
plasma reninb) of piperidine renin inhibitors with hydrophilic exten-
sions pointing into the S3 sub-pocket
[7] A.M. DelliPizzi, S.D. Hilchey, C.P. Bell-Quilley, Natriuretic
action of angiotensin(1–7), Br. J. Pharmacol. 111 (1994) 1–3.
[8] G.N. Swanson, J.M. Hanesworth, M.F. Sardinia, J.K. Coleman,
J.W. Wright, K.L. Hall, A.V. Miller-Wing, J.W. Stobb, V.I.
Cook, E.C. Harding, J.W. Harding, Discovery of a distinct
binding site for angiotensin II (3–8), a putative angiotensin IV
receptor, Regul. Pept. 40 (1992) 409–419.
[9] M. Azizi, T.-T. Guyene, G. Chatellier, J. Me´nard, Blood pres-
sure effects of acute renin or angiotensin converting enzyme
inhibition in essential hypertension, Journal of Hypertension 12
(1994) 419–427.
[10] J.M. Neutel, R.R. Luther, R.S. Boger, M.A. Weber, Immediate
blood pressure effects of the renin inhibitor enalkiren and the
ACE inhibitor enalaprilat, Am. Heart 122 (1991) 1094–1100.
[11] M.A. Weber, Clinical experience with the angiotensin II receptor
antagonist losartan, Am. J. Hypertens. 5 (1992) 247S–251S.
[12] A.K. El Amrani, J. Me´nard, M.F. Gonzales, J.B. Michel, Effects
of blocking the angio II receptor, ACE and renin activity on the
renal hemodynamics of normotensive guinea pigs, J. Cardiovasc.
Pharmacol. 22 (1993) 231–239.
a For assay conditions see Ref. [20]. The IC50 values depicted are
mean values of two to five independent determinations.
b For assay conditions see Ref. [27]. The IC50 values depicted are
mean values of two or three independent determinations.
keys and in double transgenic rats confirm the potential
of this compound (data not shown); but, unfortunately,
it shows pharmacokinetic properties clearly inferior to
those of compound 14.
[13] N.K. Hollenberg, N.D.L. Fischer, Renal circulation and block-
ade of the RAS. Is ACE inhibition the last word?, Hypertension
26 (1995) 602–609.
4. Conclusions
[14] P. van Paassen, D. de Zeeuw, P. de Jong, Renal and systemic
effects of the renin inhibitor remikiren in patients with essential
hypertension, J. Cardiovasc. Pharmacol. 26 (1995) 39–45.
[15] S. McMahon, J.A. Cutler, J. Stamler, Antihypertensive drug
treatment: potential, expected and observed effects on stroke and
coronary heart disease, Hypertension 13 (suppl. I) (1989) 145–
150.
[16] H.D. Kleinert, Recent developments in renin inhibitors, Exp.
Opin. Invest. Drugs 3 (1994) 1087–1104.
[17] P. Raddatz, Recent developments in renin inhibitors: part I,
Exp. Opin. Ther. Patents 4 (1994) 489–504.
The optimization of the piperidine renin inhibitor
series with respect to in vitro and in vivo potency, as
well as physicochemical and pharmacokinetic proper-
ties, has led to the identification of the candidate com-
pound 14. It has been profiled in pharmacodynamic
models of blood pressure reduction and in chronic
experiments in double transgenic rats harboring both
the human angiotensinogen and the human renin gene.
The data obtained clearly demonstrate its potential not
only as an antihypertensive drug, but also as a drug for
prevention and treatment of end organ damage in the
tissual systems of the kidney and the heart.
[18] P. Raddatz, Recent developments in renin inhibitors: part II,
Exp. Opin. Ther. Patents 4 (1994) 1347–1359.
[19] H.D. Kleinert, Renin inhibition, Cardiovasc. Drug Ther. 9
(1995) 645–655.
[20] E. Vieira, A. Binggeli, V. Breu, D. Bur, W. Fischli, R. Gu¨ller, G.
Hirth, H.P. Ma¨rki, M. Mu¨ller, C. Oefner, M. Scalone, H.
Stadler, M. Wilhelm, W. Wostl, Substituted piperidines—highly
potent renin inhibitors due to induced fit adaptation of the active
site, Bioorg. Med. Chem. Lett. 9 (1999) 1397–1402.
[21] R. Gu¨ller, A. Binggeli, V. Breu, D. Bur, W. Fischli, G. Hirth, C.
Jenny, M. Kansy, F. Montavon, M. Mu¨ller, C. Oefner, H.
Stadler, E. Vieira, M. Wilhelm, W. Wostl, H.P. Ma¨rki, Pipe-
ridine renin inhibitors—compounds with improved physico-
References
[1] G.A. McGregor, N.D. Markandu, J.E. Roulston, J.C. Jones, J.J.
Morton, Maintenance of blood pressure by the renin angiotensin
system in normal man, Nature 291 (1981) 329–331.
[2] B. Waeber, J. Nussberger, H.R. Brunner, The renin–angiotensin
system: role in experimental and human hypertension, in: A.
Zanchetti, R.C. Tarazi (Eds.), Pathophysiology of Hypertension-
Regulatory Mechanisms. In: Handbook of Hypertension, vol. 8,
Elsevier, Amsterdam, 1986, pp. 489–519.
[3] M.A. Pfeffer, E. Braunwald, L.A. Moye, L. Basta, E.J. Brown,
Jr, T.E. Cuddy, B.R. Davis, E.M. Geltman, S. Goldman, G.C.
Flaker, C.M. Hawkins, Effect of captopril on mortality and
morbidity in patients with left ventricular dysfunction after
myocardial infarction. Results of the survival and ventricular
enlargement trial, N. Engl. J. Med. 327 (1992) 669–677. The
SAVE Investigators.
[4] S. Kim, H. Iwao, Molecular and cellular mechanisms of an-
giotensin II-mediated cardiovascular and renal diseases, Pharma-
col. Rev. 52 (2000) 11–34.
chemical properties, Bioorg. Med. Chem. Lett.
1403–1408.
9 (1999)
[22] J. Maibaum, V. Rasetti, H. Ru¨eger, N.C. Cohen, R. Go¨schke,
R. Mah, J. Rahuel, M. Gru¨tter, F. Cumin, J.M. Wood, Design
of novel potent, non-peptide and orally active renin inhibitors,
in: M. Yamazaki (Ed.), Medicinal Chemistry: Today and To-
morrow, Proceedings of the AFMC International Medicinal
Chemistry Symposium, Tokyo, 1995, Blackwell, UK, 1997, pp.
155–162.
[23] J. Rahuel, V. Rasetti, J. Maibaum, H. Ru¨eger, R. Go¨schke, N.C.
Cohen, S. Stutz, F. Cumin, W. Fuhrer, J.M. Wood, M.G.
Gru¨tter, Structure-based drug design: the discovery of novel
nonpeptide orally active inhibitors of human renin, Chem. Biol.
7 (2000) 493–504.

H.P. Ma¨rki et al. / Il Farmaco 56 (2001) 21–27
27
[24] V. Breu, H.P. Maerki, E. Vieira, W. Wostl, Novel piperidine
derivatives, International Patent Application PCT/EP00/03555
(Priority: 27 April 1999, Filing Date: 20 April 2000).
[25] Z.-I. Horii, Y. Matsumoto, T. Momose, Synthetic studies on
anthracylinones. IX. Lithiation of N,N-dimethyl-naphthalene-
methylamines and a new synthetic pathway to 2,3-naphthalides,
Chem. Pharm. Bull. 19 (1971) 1245–1256.
[26] V. Breu, D. Bur, H.P. Maerki, E. Vieira, W. Wostl, Novel
piperidine derivatives, International Patent Application PCT/
EP00/03597 (Priority: 27 April 1999, Filing Date: 19 April 2000).
[27] W. Fischli, J.-P. Clozel, K. El Amrani, W. Wostl, W. Neidhart,
H. Stadler, Q. Branca, Ro 42-5892 is a potent orally active renin
inhibitor in primates, Hypertension 18 (1991) 22–31.
[28] J. Bohlender, A. Fukamizu, A. Lippoldt, T. Nomura, R. Dietz,
J. Menard, K. Murakami, F.C. Luft, D. Ganten, High human
renin hypertension in transgenic rats, Hypertension 29 (1997)
428–434.
[29] E. Mervaala, D.N. Muller, F. Schmidt, J.-K. Park, V. Gross, M.
Bader, V. Breu, D. Ganten, H. Haller, F.C. Luft, Blood pres-
sure-independent effects in rats with human renin and an-
giotensinogen genes, Hypertension 35 (2000) 587–594.
[30] J. Maibaum, N.C. Cohen, J. Rahuel, Ch. Schell, H.-P. Baum, P.
Rigollier, W. Schilling, J. M. Wood, Design and synthesis of
novel, fully non-peptide transition state mimetic renin inhibitors
bearing an O-alkyl substituted salicylamide (Ps3p–P3)-moiety with
high oral in vivo potency, in: XVth EFMC International Sympo-
sium on Medicinal Chemistry, Edinburgh, UK, 6–10 September,
1998, abstract book p. 231.
[31] R. Go¨schke, V. Rasetti, N.C. Cohen, J. Rahuel, M. Gru¨tter, S.
Stutz, H. Ru¨eger, W. Fuhrer, J. M. Wood, J. Maibaum, Novel
2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-oc-
tanecarboxamide transition state peptidomimetics are potent and
orally active inhibitors of human renin, in: XVth EFMC Interna-
tional Symposium on Medicinal Chemistry, Edinburgh, UK,
6–10 September, 1998, abstract book p. 229.
[32] J. Maibaum, S. Stutz, R. Go¨schke, P. Rigollier, Y. Yamaguchi,
W. Schilling, J. M. Wood, Structural modification of the P2%
position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-
phenyl-octanecarboxamides: Discovery of a potent nonpeptide
human renin inhibitor active after once daily dosing in mar-
mostets, in: XVth EFMC International Symposium on Medici-
nal Chemistry, Edinburgh, UK, 6–10 September, 1998, abstract
book p. 230.
[33] D.N. Muller, R. Dechend, E.M. Mervaala, J.K. Park, F.
Schmidt, A. Fiebeler, J. Theuer, V. Breu, D. Ganten, H. Haller,
F.C. Luft, NF-kappaB inhibition ameliorates angiotensin II-in-
duced inflammatory damage in rats, Hypertension 35 (2000)
193–201.
.