Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase.

Article abstract of DOI:10.1016/S0968-0896(02)00034-2

The pyrazolopyridine stimulators of soluble guanylate cyclase BAY 41-2272 and 41-8543 were oxidised in rats and dogs at their 5-pyrimidinyl-cyclopropyl and -morpholino residue. These metabolites activate the soluble guanylate cyclase, induce vasoelaxation and thereby may contribute to the in vivo activity of BAY 41-2272 and BAY 41-8543.

Full text of DOI:10.1016/S0968-0896(02)00034-2

Bioorganic & Medicinal Chemistry 10 (2002) 1711–1717
Metabolites of Orally Active NO-Independent Pyrazolopyridine
Stimulators of Soluble Guanylate Cyclasey
Alexander Straub,a,* Jordi Benet-Buckholz,b Rita Frode,b Armin Kern,c
Christian Kohlsdorfer,d Peter Schmitt,a Thomas Schwarz,d Hans-Martin Siefertd
and Johannes-Peter Stasche
aInstitute of Medicinal Chemistry, Pharma Research Centre, Bayer AG, D-42096Wuppertal, Germany
bCentral Research, Division of Structural Research, Bayer AG, D-51368 Leverkusen, Germany
cDepartment of Drug Metabolism and Isotope Chemistry, Pharma Research Centre, Bayer AG, D-42096Wuppertal, Germany
dDepartment of Preclinical Pharmacokinetics, Pharma Research Centre, Bayer AG, D-42096Wuppertal, Germany
eInstitute of Cardiovascular Research, Pharma Research Centre, Bayer AG, D-42096Wuppertal, Germany
Received 30 October 2001; accepted 17 January 2002
Abstract—The pyrazolopyridine stimulators of soluble guanylate cyclase BAY 41-2272 and 41-8543 were oxidised in rats and dogs
at their 5-pyrimidinyl-cyclopropyl and -morpholino residue. These metabolites activate the soluble guanylate cyclase, induce vaso-
elaxation and thereby may contribute to the in vivo activity of BAY 41-2272 and BAY 41-8543. # 2002 Elsevier Science Ltd. All
rights reserved.
Introduction
After oral dosing in animals, 1 and 2 were quickly oxi-
dizes at their 5-pyrimidinyl-cyclopropyl and morpholino
Soluble guanylate cyclase (sGC)2 is a heterodimeric (a/
ß) heme-protein that converts GTPto cGMP, which is
involved in a wide range of physiological processes in
humans and animals. Its natural stimulator is nitric
oxide (NO) which acts by coordination to the heme
moiety. Organic nitrates like glycerol trinitrate or iso-
sorbide dinitrate have been used for decades as a treat-
ment for angina pectoris. In vivo they generate NO and
thus mimic the action of the endogenous mediator. The
major drawback of this therapy is the development of
tolerance after repeated administrations. Recently, we
and others disclosed a novel class of NO-independent
sGC-stimulators with vasodilating activities, which on
the one hand stimulate sGC directly and on the other
hand sensitize the enzyme towards its native activator
NO.3À5 Starting from YC-13 as lead structure our
research culminated in the pyrazolopyridines BAY 41–
2272 (1) and BAY 41–8543 (2) as the most promising
ones out of a series of about two thousand of newly
synthesized derivatives.4
residues, respectively (Scheme 1). However, a long last-
ing blood pressure (bp)-lowering effect was found. As
an explanation one might postulate that the metabolites
could contribute to this pharmacological effect as well.
In order to test this hypothesis we went for their isola-
tion from biological material, proceeded with structural
determinations and synthesis and finally studied the
pharmacological and pharmacokinetic properties of
both main metabolites of 1 and 2.
Isolation, Purification and Structural Determination
The main metabolites of BAY 41–2272 and BAY 41–
8543 were isolated from Wistar rat hepatocyte suspen-
sions. Hepatocytes were isolated as described pre-
viously.6 Incubations were performed at cell densities of
107 to 2Â108 cells per 20 mL for 4 h under a 95% O2/5%
CO2 atmosphere at 37 ꢀC. Metabolites were isolated
from supernatants by solid phase extraction followed by
preparative HPLC using RP18 material and tri-
fluoroacetic acid (0.1%)/acetonitrile as eluent system.
Structural determinations of the metabolites from bio-
logical matrices were performed by 2D-NMR and MS.
After synthesis of the proposed structures, they showed
to be identical with respect to LC retention times, mass
yPart of this work was presented previously; see ref 1.
*Corresponding author at current address: Bayer AG, Agricultural Cen-
tre, Bldg. 6550, D-40789 Monheim, Germany. Tel.: +49-2173-384972;
fax: +49-2173-384880; e-mail: alexander.straub.as@bayer-ag.de
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00034-2

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A. Straub et al. / Bioorg. Med. Chem. 10 (2002) 1711–1717
Scheme 1. Main metabolites of BAY 41-2272 and BAY 41-8543 in rats and dogs.
Figure 1. Numbering, HMBC contacts and single crystal X-ray structure of metabolite 14.
spectra and by NMR spectroscopy. An X-ray analysis
of the synthetic material gave the final proof for the
structural proposal.7 Details on the structure of 3 were
presented elsewhere,8 whereas 14 is shown in Figure 1.
Carbon chemical shifts were detected by two-dimen-
sional HMQC and HMBC methods. The data are given
in Table 1. Three different NH and OH protons could
be detected. There were some important HMBC con-
tacts in the HMBC spectrum. The signal of the NH
proton at 8.05 ppm showed contacts to C-5 in the pyr-
imidinyl-moiety and C-3 in the morpholinyl-moiety. In
addition, the HMBC contact between H-2 in the mor-
pholinyl part and C-4 of the pyrimidine part also
proved the NH bridge. The HMBC contact between
H-3 in the morpholinyl moiety and C-5 in the pyr-
imidine ring served as a further confirmation of the
assignment.
esis was therefore established recently by the group of
DeMeijere et al.8
The synthesis of the metabolite 14 is shown in Scheme 3.
In the course of our large chemistry program which was
aimed to optimize the lead structure, we learned that
construction of triaminopyrimidine moieties via a
hydroxyethyl-substituted aminomalononitrile C3 build-
ing block might offer some obstacles. Furthermore, all
attempts to react nitro-, nitroso- or amino-substituted
malonic acid diesters or malonodinitriles with the pyr-
azolopyridinyl amidine failed and did not lead to the
desired 5-nitrogen-functionalized pyrimidine. Therefore,
1
a
Table 1. 300 MHz À H/13C NMR data of 14 in DMSO-d6
d (H)
ppm
Mult. Int d (C) Assignment corresponding to Fig. 1
ppm
2.98; 3.20 D; M 1; 1 51.1
H-5; C-5 (morpholinyl-ring)
H-6; C-6 (morpholinyl-ring)
H-3; C-3 (morpholinyl-ring)
H-2; C-2 (morpholinyl-ring)
CH2 (fluorobenzyl)
OH (morpholinyl-ring)
NH2 (pyrimidine)
(fluorobenzyl)
Chemistry9
3.28
4.55
4.83
5.80
5.95
6.22
7.13
M
BS
D
S
D
2
1
1
2
1
2
2
53.9
75.5
76.5
43.8
—
The first synthesis of the hydroxycyclopropyl metabolite
3 proceeded as depicted in Scheme 2.10 Condensation of
2-fluorophenylhydrazine with the sodium salt of ethyl
cyanopyruvate yielded an ethyl 5-aminopyrazole-3-car-
boxylate which was cyclized with dimethylaminoacro-
lein to the 1H-pyrazolo[3,4-b]pyridine-3-carboxylate 5.
Conversion of the ester into an amidine group yielded 9,
which was condensed with ethyl ethoxymethyleneacetate
to the pyrimdine 10. The ester group was subsequently
transformed into the cyclopropanol group (3). The
construction of the cyclopropyl moiety was adapted
from a protocol of Imamoto11 by using the Kagan
reagent SmI2. The yield was quite low, which could be
due to the presence of a free amino group and several
heteroatoms in the molecule. A more elaborate synth-
BS
M
—
124.7;
129.9
115.4
7.23
7.35
M
M
1
(fluorobenzyl)
H-5/C-5 (pyrazolopyridinyl);
fluorobenzyl
NH (morpholinyl-ring)
H-6/C-6 (pyrazolopyridinyl)
H-4/C-4 (pyrazolopyridinyl)
C-5 (pyrimidine)
C-9 (pyrazolopyridinyl)
C-4 (pyrimidine)
C-F (fluorobenzyl)
1;1 117.8;
129.9
8.05
8.61
9.06
—
—
—
D
D
D
—
—
—
—
1
1
1
1
1
—
148.9
133.8
102.9
151.7
156.9
160.7
—
1
—
aCarbon-chemical shifts were determined by HMQC, HMBC.

A. Straub et al. / Bioorg. Med. Chem. 10 (2002) 1711–1717
1713
Scheme 2. Reagents and conditions: (a) NC–CH¼C(ONa)CO2Et/TFA, dioxane, reflux, 8 h; (b) Me2NCH¼CH–CHO/TFA/dioxane, reflux, 3 days,
50% for steps (a) and (b); (c) NH3/MeOH, rt, 2 days, quant; (d) TFAA/pyridine, rt, 8 h, quant; (e) MeONa/MeOH, rt, 2 h, quant; (f) NH4Cl/HAc,
MeOH, reflux, 8 h; (2) Na2CO3/H2O, rt, 76%; (g) EtOCH¼C(CN)CO2Et/toluene, 110 ꢀC, 5 h, 21%; (h) (1) CH2I2/Sm/THF, 50 ꢀC, 70 min; (2) 1 N
HCl, extract; (3) RP18 chromatography, 1%.
Scheme 3. Reagents and conditions: (a) Ph–N¼N–CH(CN)2/NaOMe/DMF, 110 ꢀC, 12 h, 73%; (b) (1) Raney–Ni/H2/DMF, 65 bar, 62 ꢀC, 22 h; (2)
2.5 N HCl, precipitate; (3) NaHCO3, 59%; (c) TBDMS–OCH2CHO/Molsieve 3A/NaCNBH3/AcOH/MeOH, rt, 5 h, 38%; (d) TBAF/THF, rt, 2 h;
(e) OHC–CHO/40% in water, rt, 12 h, 10% (over steps d and e).
we tried a pathway which proceeds in analogy to the
route published by Singh and Lesher.12 Phenylazoma-
lononitrile was prepared according to ref 13 and reacted
smoothly with the amidine 9 to give the pyrimidine
nucleus. The masked amino group was liberated via
catalytic hydrogenation under forced conditions to yield
the triaminopyrimidine 11. This compound is also a
valuable synthon since it can serve as starting material
for numerous N-derivatizations. It was selectively
converted to the N-5-hydroxyethyl derivative 12 by
reductive amination with TBDMS-protected hydroxy-
acetaldehyde. After deprotection of the TBDMS group
with TBAF, the ring-constructing key step of the
synthesis is performed in a one-pot procedure by sub-
sequent addition of aqueous glyoxal solution. Whereas
several examples of reactions between aminoalcohols
and glyoxal equivalents can be traced in the literature,14
there is no precedent for the current type of bicyclic ring
formation. The final material 14 can be isolated after
chromatographic purification on reversed-phase silica
gel. The use of alcohols as eluents or solvents for this
compound is prohibitive since they easily exchange with
the semi-aminal part.
and b1 subunits was isolated from a batch reactor run
via several chromatographic steps yielding 1 mg/2.5 L
culture broth. The basal activity of the purified enzyme
.
Enzyme activity was determined by the formation of
[32P]cGMP from a-[32P]GTP.
was 154 nmol minÀ1 mgÀ1 in the presence of Mg2+
Figure 2. Stimulation of purified sGC by 3 (-*-) and 14 (-*-) in the
absence and stimulation of purified sGC by 3 (-!) and 14 (-!-) in the
presence of 10 mM SIN-1. The specific sGC activity is expressed as x-
fold stimulation versus specific basal activity (154ꢁ11 nmol/mg/min
in the presence of Mg2+). The data represent means ꢁSEM from four
determinations. The assay has been performed as previously described
by us.4c
Biology3,4
Measurement of sGC activity
Rat lung sGC overexpressed in a baculovirus/Sf9 sys-
tem using a defined mixture of viruses encoding the a1

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A. Straub et al. / Bioorg. Med. Chem. 10 (2002) 1711–1717
Tests on aortic rings
Blood pressure measurements
Aortic rings (1.5 mm) from Chinchilla rabbits of either
sex were suspended under an initial tension of approxi-
mately 4 g in 5 mL Krebs–Henseleit solution at 37ꢀ C.
Contractions to 3Â10À8 g/mL phenylephrine leading to
a submaximum contraction were followed by a series of
16 washing cycles and a resting period of 28 min. The
test compounds were added at the beginning of the last
resting period.
Male Wistar rats weighting 300–250 g were anaesthetized
with thiopental NycomedTM 100 mg/kg ip. A tracheotomy
was performed and catheters were inserted into the
femoral artery for blood pressure measurement and in the
femoral vein for substance administration. The animals
were ventilated with room air and their body temperature
was controlled. The compounds were administered orally
as a solution in TranscutolTM/CremophorTM EL/water
(10/20/70=v/v/v) in a volume of 1 mL/kg by gavage. For
iv administration, they were dissolved in a solution of
TranscutolTM/CremophorTM EL/0.9% NaCl (10/10/
80=v/v/v), and the administration volume was 1 mL.
Table 2. In vitro potency of compounds
Compd
Inhibition of contraction
of aortic rings
IC50, mM
Biological results
BAY 41-2272
3
BAY 41-8543
14
YC-1
0.3
0.4
0.2
1.2
10
We found considerable biological activity for both parent
compounds and metabolites. 3 and 14 are potent sGC-
stimulators, that at concentrations from 0.01 to 100 mM
Figure 3. Effect of oral BAY 41-2272 on MAPin anaesthetized Wistar
rats: -*- Control (n=6), -!- 0.3 mg/kg (n=4), -~- 1.0 mg/kg (n=5),
-&- 3.0 mg/kg (n=4).
Figure 5. Effect of intravenous 3 on MAPin anaesthetized Wistar
rats. -*- Vehicle (n=4), -&- 3: 0.1 mg/kg (n=2), -~- 3: 0.03 mg/kg
(n=2), -!- 3: 0.01 mg/kg (n=2).
Figure 4. Effect of intravenous BAY 41-2272 on MAPin anaes-
thetized Wistar rats. -*- Control (n=4), -^- 0.1 mg/kg (n=4), -!-
0.03 mg/kg (n=4), -~- 0.01 mg/kg (n=5), -&- 0.003 mg/kg (n=4).
Figure 6. Mean plasma concentrations versus time curves of BAY 41-
2272 (-*-) and the metabolite 3 (-*-) in Wistar rats after single oral
administration of 5 mg/kg BAY 41-2272.

A. Straub et al. / Bioorg. Med. Chem. 10 (2002) 1711–1717
1715
stimulte recombinant sGC from 1.3- to 155-fold and
from 1.4- to 155-fold, respectively (Fig. 2). In combina-
tion 3 and 14 and the NO donor SIN-1 potentiate over a
wide range of concentrations. Thus, the profile of both
metabolites at the isolated enzyme is comparable to that
of their parent compounds.4a,d Through their inter-
action with sGC, both metabolites elicited a concen-
tration-dependent vasorelaxation in vitro.4a The
compounds inhibited the constriction of rabbit aortic
rings induced by phenylephrine (3Â10À8 g/mL)
expressed as IC50 values (Table 2). For demonstration
of the in vivo efficacy the bp-lowering effect of the sGC
stimulators was shown in anaesthetized Wistar rats as
previously described by us.4b,c BAY 41-2272 is a potent
bp-lowering substance in these rats after oral adminis-
tration (Fig. 3). After iv administration BAY 41-2272
and 3 showed comparable in vivo activity (Figs 4 and
5). The plasma concentrations of BAY 41-2272 and its
metabolite 3 in rats and dogs are shown in Fig. 6 and 7,
respectively. The concentration of 3 is about twice the
amount of BAY 41–2272. Dogs behave similarly in this
respect, whereas after iv dosing a slower increase in
plasma levels of 3 was noticed in this species (Fig. 8).
BAY 41-2272 is a high-clearance drug with a short half-
life (rat iv 0.5 h; po 1 h; dog iv 1 h; po 2 h).
Figure 7. Mean plasma concentrations versus time curves of BAY 41-
2272 (-*-) and the metabolite 3 (-*-) in Beagle dogs after oral
administration of 2 mg/kg BAY 41-2272.
Figure 10. Effect of intravenous 14 on MAPin anaesthetized Wistar
rats. -*- Control, -^- 14: 0.3 mg/kg (n=10), -&- 14: 0.1 mg/kg
(n=10).
Figure 8. Mean plasma concentrations versus time curves of BAY 41-
2272 (-*-) and the metabolite 3 (-*-) in Beagle dogs after intravenous
infusion of 1 mg/kg BAY 41-2272.
Figure 11. Effect of intravenous BAY 41-8543 on MAPin anaes-
thetized rats. -*- Control (n=8), -!- 0.03 mg/kg (n=4), -&- 0.01
mg/kg (n=3), -^- 0.03 mg/kg (n=8), -~- 0.1 mg/kg (n=8), - - 0.3
mg/kg (n=8).
Figure 9. Effect of oral BAY 41-8543 on MAPin anaesthetized Wistar
rats. -*- Control (n=10), -!- 0.1 mg/kg (n=4), -&- 0.3 mg/kg
(n=4), -^- 1 mg/kg (n=4).

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A. Straub et al. / Bioorg. Med. Chem. 10 (2002) 1711–1717
properties. Due to their persistance in plasma, they may
contribute to the vasodilation seen in vivo after oral
administration of the parent compounds.
References and Notes
1. Straub, A.; Benet-Buchholz, J.; Frode, R.; Kern, A.;
Kohlsdorfer, C.; Schmitt, P.; Schwarz, T.; Siefert, H.-M.;
Stasch, J.-P. Abstracts of Papers, 222nd National Meeting of
the American Chemical Society, Chicago, IL, Aug 25–30,
2001; MEDI-253.
2. (a) For recent reviews see Hobbs, A. J. Trends Pharmacol.
Sci. 1997, 18, 484. (b) Moncada, S.; Palmer, R. M.; Higgs,
E. A. Pharmacol. Rev. 1991, 43, 109. (c) Furchgott, R. F.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1870. (d) Murad, F.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1857. (e) Ignarro, L. J.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1882.
Figure 12. Mean plasma concentrations versus time curves of BAY
41-8543 (-*-) and 14 (-*-) in Beagle dogs after oral administration of
1 mg/kg BAY 41-8543.
3. (a) Ko, F. N.; Wu, C.-C.; Kuo, S.-C.; Lee, F.-Y.; Teng, C.-
M. Blood 1994, 84, 4226. (b) Wu, C. C.; Ko, F. N.; Kuo, S. C.;
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Friebe, A.; Schultz, G.; Koesling, D. EMBO J. 1996, 15, 6863.
(d) Mulsch, A.; Bauersachs, J.; Schafer, A.; Stasch, J.-P.; Kast,
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E. M.; Wunder, F.; Kast, R.; Robyr, C.; Hoenicka, M.; Gerzer,
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E.; Pleis, U.; Schroder, H.; Schroeder, W.; Stahl, E.; Steinke,
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Stasch, J.-P.; Dembowsky, K.; Perzborn, E.; Stahl, E.;
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Chana, S. S.; Charles, I. G.; Fernandez, P. A.; Glen, R. C.;
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D. J.; Meillerais, S.; Powell, K. L.; Reynolds, K.; Spacey,
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Schonafinger, K.; Strobel, H.; WO 00/02851, 2000 Chem.
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Strobel, H.; WO 00/09496, 2000; Chem. Abstr., 2000, 12,
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Groehn, V.; WO 99/42444, 1999; Chem. Abstr, 1999, 131,
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Figure 13. Mean plasma concentrations versus time curves of BAY
41-8543 (-*-) and the metabolite 14 (-*-) in Wistar rats after single
oral administration of 5 mg/kg BAY 41-8543.
Figure 9 shows the bp-lowering effect of BAY 41-8543
in rats after oral administration. The compound is
about 3-fold more potent than BAY 41-2272 in this
model (Fig. 3). 14 is the main metabolite of BAY 41-
8543 in different species. For comparision of BAY 41-
8543 and 14, the bp-lowering effect in anaesthetized
Wistar rats after iv administration was investigated.
Figure 10 shows the effect of 14 on bp after iv applica-
tion in rats, which is about 3- to 10-fold less potent than
BAY 41-8543 but displayed a longer lasting effect com-
pared to BAY 41-8543 (Fig. 11). BAY 41–8543 was
investigated in rats and dogs after oral dosing showing
that it is metabolized to 14 more intensely in dogs (Fig.
12) as compared to rats, where plasma concentrations of
14 are higher than the levels of BAY 41-8543 (Fig. 13).
6. Kern, A.; Bader, A.; Pichlmayr, R.; Sewing, K. F. Biochem.
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DeMeijere, A. Abstracts of Papers, 22nd National Meeting of
the American Chemical Society, Chicago, IL, Aug 25–30,
2001; MEDI-254.
Conclusions
After po or iv administration of the guanylate cyclase
stimulators BAY 41-2272 and BAY 41-8543 in rats, we
have isolated two main metabolites, 3 and 14, respec-
tively. These metabolites display strong bp-lowering
9. (a) All final compounds were characterized by NMR and
mass spectrometry. For experimental details see: Straub, A.;
Feurer, A.; Alonso-Alija, C.; Stasch, J.-P.; Perzborn, E.; Hut-
ter, J.; Dembowsky, K.; Stahl, E.; WO 00/06568, 2000; Chem.

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