Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, an ETa selective endothelin antagonist1

Article abstract of DOI:10.1021/jm000349x

Sitaxsentan (3, TBC11251) (Wu et al. J. Med. Chem. 1997, 40, 1690) is an orally active ET_A selective endothelin antagonist that attenuates pulmonary vascular hypertension and cardiac hypertrophy in rats (Tilton et al. Pulm. Pharmacol. Ther. 200

Full text of DOI:10.1021/jm000349x

J . Med. Chem. 2001, 44, 1211-1216
1211
Acyl Su bstitu tion a t th e Or th o P osition of An ilid es En h a n ces Or a l
Bioa va ila bility of Th iop h en e Su lfon a m id es: TBC3214, a n ET
En d oth elin An ta gon ist1
A
Selective
†
†
Chengde Wu,* E. Radford Decker, Natalie Blok, J ian Li, Andree R. Bourgoyne, Huong Bui, Karin M. Keller,
Vippra Knowles, Wen Li, Fiona D. Stavros, George W. Holland, Tommy A. Brock, and Richard A. F. Dixon§
‡
†,‡
Departments of Chemistry, Pharmacology, and Preclinical Toxicology, Texas Biotechnology Corporation, 7000 Fannin,
Suite 1920, Houston, Texas 77030
Received August 11, 2000
Sitaxsentan (3, TBC11251) (Wu et al. J . Med. Chem. 1997, 40, 1690) is an orally active ET
A
selective endothelin antagonist that attenuates pulmonary vascular hypertension and cardiac
hypertrophy in rats (Tilton et al. Pulm. Pharmacol. Ther. 2000, 13, 87). It has demonstrated
efficacy in a phase II clinical trial for congestive heart failure (Givertz et al. Circulation 2000,
1
01, 2922). During the discovery of 3, we observed several structure-oral bioavailability
relationships. To investigate whether there is any generality in these trends, we synthesized
some similar pairs of compounds in the latest series (Wu et al. J . Med. Chem. 1999, 42, 4485)
and evaluated their oral properties. In both series, an acyl group at the 2-position of the anilide
of these thiophene sulfonamides improved oral bioavailability. As a result of this exercise,
TBC3214 (17) was identified as a sitaxsentan follow-on candidate. It is very potent (IC50 for
ET
A
) 40 pM) and highly selective for ET
A B
vs ET receptors (400 000-fold), with a half-life of
>4 h and oral bioavailability of 25% in rats, 42% in cats, and 70% in dogs.
In tr od u ction
sulfonamides 1-6,10,2 3 (sitaxsentan or TBC11251)
4
being in phase II trials for congestive heart failure and
The vaso-constrictive peptide endothelin has been
implicated as a causative factor in a number of disease
states, and as such it has become a popular target
1
1
pulmonary hypertension. An analysis of the oral
bioavailability data revealed the following trends in
relationship with structure (Chart 1): (A) Changing the
linker between thiophene and benzodioxole from amide
to ketomethylene increased oral bioavailability greatly
6
among drug discovery groups. Mimicking binding of a
peptide to its receptor or blocking of such binding by
small molecule antagonists is an essential first step in
drug discovery, but the successful advancement of such
small molecule antagonists to clinical candidates often
depends on building appropriate drug metabolism and
pharmacokinetics (DMPK) properties into the lead
scaffolds. In this report we present some oral bioavail-
ability structure-activity relationships (SAR) which we
hope will be useful to the scientific community in the
discovery of therapeutics.
(from 0% for 1 to 30% for 2). This was assuming that
change from Br to Cl on the isoxazole ring did not
influence significantly on oral bioavailability. (B) Chang-
ing the 4-chloroisoxazole to 4-methylisoxazole doubled
oral bioavailability (from 60% for 3 to ∼100% for 4). (C)
Third, an acetyl group on the 6-position of the benzo-
dioxozole afforded compound 6 good oral bioavailability
(27%), comparing with unsubstituted 1 (0%) or the
cyano compound 5 (8%).
For successful oral action, the candidate molecule
must not only be adsorbed but additionally it must
partition to the appropriate target tissue. Lipophilicity
has long been recognized as a major determinant of
We needed to ascertain if the three above-mentioned
trends are general for this series or only compound-
specific, not only for our drug optimization purpose but
also for gaining a deeper understanding of medicinal
chemistry. Therefore, we synthesized three groups of
compounds (19, 20; 21-23; 24, 25, and 16-18) where
the benzodioxole moiety was replaced by a phenyl group.
7
absorption, but more recently, the importance of other
molecular descriptors such as polar surface area (PSA)
has been recognized.8
,9
For endothelin antagonists, receptors on the surface
of vascular endothelial cells are the target, and thus,
plasma levels of test compounds have shown a good
correlation with in vivo biological activity. Thus, mea-
suring plasma levels of test compounds after oral
administration have proven a useful technique for
directing the synthesis of analogues.
Resu lts a n d Discu ssion
Syn th etic Ch em istr y. The synthesis of 16-18 is
delineated in Scheme 1 starting from commercially
available 2,4-dimethylaniline 7. A boron trichloride
1
2
mediated Friedel-Crafts acylation reaction converted
to acetophenone 8 or isobutyrophenone 9 in good
7
We have reported the synthesis, biological assays, and
pharmacokinectics of a series of benzodioxole thiophene
yields, using acetonitrile or isobutyronitrile, respec-
tively. After some unsuccessful attempts to reduce the
keto group directly to a methylene, compound 11 was
obtained via stepwise reduction of 8 to the alcohol 10
with borane and then a further reduction of 10 with
triethylsilane in TFA. The anilines 11, 8, and 9 were
*
Phone: (713) 796-8822 ext 130. Fax: (713) 796-8232. E-mail:
cwu@tbc.com.
†
Department of Pharmacology.
Department of Preclinical Toxicology.
Senior VP, Research and CSO.
‡
§
1
0.1021/jm000349x CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001

1
212 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 8
Wu et al.
Ch a r t 1. Structure-Oral Bioavailability (F)
Relationships of Benzodioxole Endothelin Antagonists
Sch em e 1. Synthesis of Endothelin Antagonists 16-18a
a
(
a) BCl3/RCN/1,2-dichloroethane; (b) HCl/H2O/MeOH; (c)
BH3‚THF; (d) TFA/Et3SiH; (e) THF/4-dimethylaminobenzonitrile;
(f) concentrated HCl/MeOH/70 °C.
Str u ctu r e-Or a l Absor p tion Rela tion sh ip s. The
structure-oral absorption comparisons are presented
in Chart 2. The oral absorption in rats is expressed as
(i) peak plasma concentration (Cmax) of said compounds
after oral dosing at 50 mg/kg and (ii) the area under
the curve extrapolated to infinity (AUCinf). Although
these parameters are not equivalent to oral bioavail-
ability, for comparison purposes they should offer ac-
curate enough insights.
The beneficial effect of changing an amide linker to
the corresponding ketone tether (from 1 to 2) did not
show in this trimethylphenol series. Actually such a
change (from 19 to 20) decreased oral absorption ap-
proximately by an order of magnitude. The effects of
different isoxazoles were then studied in a trimethyl-
benzyl cyanide grouping. In contrast to the promoting
effect on oral bioavailability going from 4-chloro (3) to
4-methylisoxazole (4), a similar switch (from 22 to 21)
lowered the Cmax while AUC did not change much. It is
interesting to note that when the oxygen and nitrogen
atoms in the chloroisoxazole ring were swapped posi-
tions (22 to 23), a modest increase in Cmax was observed
while AUC was 3-fold higher. The effects of ortho
substituents were then investigated. The compound
then independently coupled with thiophene acid chloride
5
1
2 using 4-dimethylaminobenzonitrile as the base to
give amides 13-15, respectively. The reaction proceeded
well using 2 equiv of the anilines 8, 9, or 11, but addition
of strong bases such as triethylamine or aqueous
inorganic bases afforded no coupling products, giving
back the aniline and decomposed acid chloride. The
deprotection of the methoxymethyl group was accom-
plished with heating in a 2:1 mixture of methanol and
concentrated HCl to reveal the desired sulfonamides
1
6-18.
1
0
The synthesis, in vitro binding, in vivo activity, and
without any ortho substitutents (24) was not orally
available at all, while the mesitylanilide (25), with two
methyl groups on the two ortho positions, respectively,
serum half-lives for compounds 19-23 and 25 have been
recently reported.5

Improved Oral Bioavailability of Thiophene Sulfonamides
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 8 1213
Ch a r t 2. Structure-Oral Absorption Relationships of Phenyl Endothelin Antagonists
had decent oral absorption. When one of the two ortho
substituents was ethyl (16), the oral absorption was still
respectable but considerably lower than the o-dimethyl
compound 25. Interestingly, when the ethyl group in
hydrogen bond. This would increase permeability13 of
these compounds across the intestinal mucosa, resulting
in increased oral availability. The fact that a cyano
group on the ortho position (5) only increased oral
bioavailability marginally seems to support such argu-
ment: the nitrile group probably can increase in vivo
aqueous solubility by merit of both its own polarity and
its effect of making the amide more acid-like. However,
being a straight triple bond, the cyano group cannot
form an internal hydrogen bond, therefore, making it
less permeable to membranes. Second, the acyl group
is highly electron withdrawing and, therefore, makes
the linker amide behave as a carboxyl group, resulting
in increased aqueous solubility of the compound.
Molecu la r Mod elin g. Molecular modeling was initi-
ated to investigate if indeed an intramolecular hydrogen
bond exists in the lowest energy conformation. The first
question was should the sulfonamide be treated as a
charged or neutral group? Since absorption usually
takes place in the intestine where pH is close to 7, and
the pKa value of the chloroisoxazolylsulfonamide hy-
drogen is estimated to be around 4.5, the compounds
should exist to a large extent in ionized form. On the
1
1
6 was changed to acetyl group, the resulting compound
7 had a marked increase in oral absorption as reflected
by a 2.6-fold increase in Cmax and a 5.8-fold increase in
AUC. The oral bioavailability of 17 was confirmed in
three species: 25% in rats, 42% in cats, and 70% in dogs.
Since a comparison between 16 and 17 is the fairest
in terms of both size of substituents and substitution
pattern, it appeared that an o-acyl group did help
increase oral bioavailability as established in both series
of compounds. To further substantiate this favorable
acyl effect on oral bioavailability in this series, an addi-
tional compound (18) was synthesized where the 2-posi-
tion of the anilide was substituted with an isopropyl-
carbonyl group. Indeed, 18 (IC50 for ETA ) 0.12 nM with
a selectivity for ETA over ETB ) 14 000) has an oral
bioavailability as good as that of 17 as demonstrated
by Cmax of 59.2 µg/mL and AUC of 297.5 h µg/mL.
One plausible explanation may be that the acyl
carbonyl and the amide NH can form an internal

1
214 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 8
Wu et al.
F igu r e 1. Lowest energy conformations at pH 7.5 for selected compounds.
Ta ble 1. Calculated Physicochemical Properties Descriptors
and 0.19 for compound 24, to -0.31 and 0.29 for
compound 17. We also calculated several physicochem-
ical property descriptors (Table 1) for compounds 1-6
and 16-25, such as dynamic polar surface area (PSAd),
dynamic averaged dipolar moment (Dd), and surface
area multiplying charge per hydrogen bond donor atom
SCHDa
(e Å )
dynamic polar
surface area (Å )
dynamic averaged
dipolar moment (D)
2
2
entry
1
2
3
4
5
6
120
112
111
111
147
131
91
103
103
111
107
120
121
118
95
7.8
7.4
6.6
7.7
7.0
9.5
7.9
9.3
8.9
6.3
9.2
8.9
7.2
6.8
7.5
7.4
1.16
0.92
1.11
0.91
0.56
0.36
0.79
0.62
0.60
1.46
1.42
0.87
0.80
0.83
0.98
0.74
(SCHD). These descriptors have been proven useful in
predicting human intestinal absorption of drug com-
1
8
1
1
1
1
2
2
2
2
2
2
6
7
8
9
0
1
2
3
4
5
pounds. For our series of compounds, there is no
correlation between PSAd or Dd and oral bioavailability.
This is probably due to the fact that our compounds exist
as charged species at physiological pH, while PSAd and
Dd are more suited for neutral species. On the other
hand, some trend can be observed between SCHD
values and measured oral bioavailability F or Cmax:
With decreasing of SCHD, F or Cmax increases. For
example, the SCHD values are 1.16, 0.56, and 0.36 for
compounds 1, 5, and 6 respectively, correlating to the
F values of 0%, 8%, and 27%. For compounds 24, 16,
25, 17, and 18, the SCHD values are 0.98, 0.79, 0.74,
0.62, and 0.60, and Cmax values are 0, 21.8, 35.9, 57.6,
and 59.2 µg/mL, respectively. The same trend holds for
other compound series shown in Chart 1: the SCHD
value decreases from 1.16 to 0.92 and F increases from
0 to 30% for 1 and 2, respectively. Similarly, going from
compound 3 to 4, SCHD drops from 1.11 to 0.91 while
F doubles. Oral bioavailability escalates from 0 to 8%
to 27% for 1, 5, and 6, whereas SCHD decreases from
1.16 to 0.56 to 0.36. Since SCHD reflects the capacity
of forming an external hydrogen bond for a compound,
a smaller SCHD value might be indicative of better
permeability or absorption and, in turn, better oral
bioavailability.
91
a
Sum of (surface area × charge of H-bond donor atom)/number
of H-bond donor atoms.
other hand, passively transported compounds are sus-
pected to cross the membrane more efficiently in their
uncharged state. Molecular modeling of previous com-
pounds of this class utilizing the charged or neutral form
of sulfonamides yielded essentially identical bioactive
conformations.14 Therefore, for this study, the lowest
energy conformation of the ionized form of compounds
1
, 6, 17, 18, and 24 were selected and are shown in
Figure 1. A Conformation search using SYBYL 6.5
package with Merck molecular force field (MMFF)16
confirmed that an intramolecular hydrogen bond forms
between the acyl carbonyl and the NH of the linker
amide in compounds 6, 17, and 18. This H-bond may
play an important role in increasing permeability as
desolvation of the polar bonds in a molecule is a
determinant of permeability.13 Due to the strong elec-
tron withdrawing effects of the acyl group, the linker
amide NH group becomes more polar. The calculated
MOPAC17 electrostatic potential (ESP) charges for N
and H atoms change from -0.21 and 0.20 for compound
15
Con clu sion
In summary, we have established the o-acyl effect on
oral bioavailability of a specific series of anilides.
Exploitation of such an effect conferred good oral
bioavailability to our second-generation endothelin an-
tagonists which are generally >10-fold more potent and
1
to -0.42 and 0.36 for compound 6, and from -0.20

Improved Oral Bioavailability of Thiophene Sulfonamides
10-fold more selective for ETA than sitaxsentan. This
effort expeditiously generated our clinical development
candidate 17 (TBC3214) with an IC50 for ETA of 40 pM
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 8 1215
N-(2-Eth yl-4,6-d im eth ylp h en yl)-3-{[(4-ch lor o-3-m eth yl-
>
5
-isoxa zolyl)a m in o]su lfon yl}-2-t h iop h en eca r b oxa m id e
(
16) Sod iu m Sa lt. The sodium salt of compound 16 is a
1
yellowish solid: mp 152-154 °C; H NMR (DMSO-d
(
6
6
) δ 10.96
(equipotent to ET-1), selectivity for ETA vs ETB of
br s, 1H), 7.68 (d, J ) 5.5 Hz, 1H), 7.41 (d, J ) 5.5 Hz, 1H),
4
42 000-fold, serum half-life of >4 h, and oral bioavail-
.91 (br s, 2H), 2.51 (q, J ) 7.7 Hz, 2H), 2.28 (s, 3H), 2.13 (s,
ability of 25-70% depending on the species.
It would be interesting to investigate if other acyl
groups have the same effect as acetyl on oral bioavail-
ability. Efforts are being spent to synthesize compounds
with acyl or other electron withdrawing groups on the
ortho position, and results will be reported in due
course.
3H), 1.99 (s, 3H), 1.05 (t, J ) 7.7 Hz, 3H); IR (KBr pellet):
-
1
1637, 1604, 1546, 1494 cm . Anal. Calcd for C19
NaO ‚0.5H O: C, 47.06; H, 4.16; N, 8.66. Found: C, 46.93;
H, 4.36; N, 8.27.
3
H19ClN -
4
S
2
2
N-(2-Acetyl-4,6-d im eth ylp h en yl)-3-{[(4-ch lor o-3-m eth -
yl-5-isoxa zolyl)a m in o]su lfon yl}-2-t h iop h en eca r b oxa m -
1
id e (17). Compound 17 is a yellowish solid: mp 58-62 °C; H
NMR (CDCl ) δ 10.44 (br s, 1H), 9.80 (br s, 1H), 7.52 (m, 3H),
3
7
3
.32 (s, 1H), 2.64 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.22 (s,
H); IR (KBr pellet): 3324, 3112, 1642, 1516, 1494 cm . Anal.
Exp er im en ta l Section
Gen er a l. Melting points were determined using a Fisher-
-1
Calcd for the sodium salt C H ClN NaO S ‚2.2H O: C, 43.09;
1
9
17
3
5
2
2
J ohns hot stage apparatus and are uncorrected. Proton NMR
H, 4.07; N, 7.93. Found: C, 42.94; H, 3.75; N, 7.71.
1
(
H NMR) spectra were recorded on a J EOL 400 MHz
N-(2-Isob u t yr yl-4,6-d im et h ylp h en yl)-3-{[(4-ch lor o-3-
m eth yl-5-isoxa zolyl)a m in o]su lfon yl}-2-th iop h en eca r box-
a m id e (18) Sod iu m Sa lt. The sodium salt of compound 18 is
spectrometer. Chemical shifts were reported in parts per
million as δ units relative to a residual solvent as internal
standard. Infrared spectra were recorded on a Bruker IFS-25
instrument as KBr pellets. Elemental analyses were performed
by Oneida Research Services, Inc. (Whitesboro, NY) and were
within 0.4% of the theoretical values unless otherwise indi-
cated. Anhydrous solvents were obtained from Aldrich Chemi-
cal Co. (Milwaukee, WI) in Sure-Seal bottles. Unless otherwise
stated, reagents and chemicals were of the highest grade from
commercial sources and were used without further purifica-
tion. ET-1 was obtained from Clinalfa Co. (Laufelfingen,
Switzerland) and ET-3 from American Peptide Co. (Sunnyvale,
1
a yellowish solid: mp 155-158 °C; H NMR (DMSO-d ) δ 11.36
6
(br s, 1H), 7.72 (d, J ) 5.2 Hz, 1H), 7.42 (d, J ) 5.2 Hz, 1H),
7.24 (s, 1H), 7.08 (s, 1H), 3.25 (m, 1H), 2.31 (br s, 6H), 2.00 (s,
3H), 0.89 (d, J ) 7.0 Hz, 6H); IR (KBr pellet): 3478, 3232,
-
1
1685, 1598, 1537, 1291 cm . Anal. Calcd for C H ClN -
2
1
21
3
NaO S ‚H O‚0.1EtOAc: C, 47.18; H, 4.40; N, 7.71. Found: C,
5
2
2
47.33; H, 4.63; N, 7.34.
P h a r m a cok in etic Assa ys. Adult Harlen Sprague Dawley
rats (∼200 mg) were used. The compound at a dose of 50 mg/
kg was administered by gavage needle in 0.5% high viscosity
carboxymethyl cellulose (5 mL/kg). Serial blood samples (200
µL) were taken at selected time points from the tail vein using
heparin coated microhematocrit tubes. Red blood cells were
removed immediately by centrifugation, and the plasma was
stored at -80 °C until analyzed by HPLC following acetonitrile
precipitation of the plasma proteins.
1
25
CA). [ I]ET-1 was obtained from Amersham (Arlington
Heights, IL). Flash chromatography was performed on silica
gel 60 (230-400 mesh, E. Merck). Thin-layer chromatography
was performed with E. Merck silica gel 60 F-254 plates (0.25
mm) and visualized with UV light, phosphomolybdic acid, or
iodine vapor. Analytical HPLC was performed on a Dynamax-
3
00A column (C18, 4.6 × 250 mm) preparative HPLC on
Dynamax-60A (83-241-c) with acetonitrile:water gradients
containing 0.1% trifluoroacetic acid. The detection wavelength
was 254 nm.
Refer en ces
(
1) The structure and biological activity of TBC3214 were dis-
closed: (a) Wu, C.; Decker, E. R.; Blok, N.; Bui, H.; Knowles,
V.; Bourgoyne, A.; Holland, G. W.; Brock, T. A.; Dixon, R. A. F.
2
-Am in o-3,5-d im eth yla cetop h en on e (8) a n d 2-Am in o-
3
,5-d im eth ylisobu tyr op h en on e (9). Compounds 8 and 9
A
Discovery of Potent, Orally Available ET Selective Endothelin
1
2a
1
Antagonists: TBC3214 and TBC3711. (i) Sixth International
Conference on Endothelins, Montreal, Canada, Oct 10-13, 1999;
Abstract P22. (ii) Abstracts of Papers, 219th National Meeting
of the American Chemical Society, San Francisco, CA, March
were synthesized using a literature procedure.
H NMR
(CDCl
3
) δ for 8: 7.41 (d, J ) 0.8 Hz, 1H), 7.05 (d, J ) 0.8 Hz,
1
1
H), 6.41 (br s, 2H), 2.58 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H). H
NMR (CDCl ) δ for 9: 7.48 (br s, 1H), 7.06 (br s, 1H), 6.71 (br
3
2
6-30, 2000; American Chemical Society: Washington, DC,
s, 2H), 3.62 (m, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.20 (d, J ) 6.6
2000; ORGN 233. (b) Decker, E. R.; Chen, S. J .; Chen, Y. F.;
Wu, C.; Dixon, R. A. F.; Brock, T. A. Evaluation of Novel, Highly
Hz, 6H).
A
Selective ET Receptor Antagonists in Hypoxia-Induced Pulmo-
1
-(2-Am in o-3,5-d im eth ylp h en yl)eth a n ol (10). To a solu-
nary Hypertension. Sixth International Conference on Endot-
helins, Montreal, Canada, Oct 10-13, 1999; Abstract P189.
2) Wu, C.; Chan, M. F.; Stavros, F.; Raju, B.; Okun, I.; Mong, S.;
Keller, K. M.; Brock, T.; Kogan, T. P.; Dixon, R. A. F. Discovery
of TBC11251, a Potent, Long Acting, Orally Active Endothelin
Receptor-A Selective Antagonist. J . Med. Chem. 1997, 40 (11),
tion of 8 (200 mg, 1.22 mmol) in anhydrous THF (10 mL) under
nitrogen was added borane‚THF complex (1 M in THF, 3.67
mL, 3.67 mmol). The reaction was stirred at room temperature
overnight before quenched with cold water and 1 N HCl. After
being stirred for another 15 min, the mixture was basified with
sodium carbonate and extracted with EtOAc. The organic layer
(
(
(
1
690-1697.
3) Tilton, R. G.; Munsch, C. L.; Sherwood, S. J .; Chen, S.-J .; Chen,
Y.-F.; Wu, C.; Blok, N.; Dixon, R. A. F.; Brock, T. A. Attenuation
of Pulmonary Vascular Hypertension and Cardiac Hypertrophy
was separated and dried (MgSO
the filtrate was concentrated on rotavap to afford 10 (170 mg,
4
), the solids were filtered, and
1
∼
85% yield) as a solid: H NMR (DMSO-d
Hz, 1H), 6.67 (d, J ) 1.4 Hz, 1H), 5.06 (d, J ) 3.0 Hz, 1H),
.75 (m, 1H), 4.53 (br s, 2H), 2.12 (s, 3H), 2.04 (s, 3H), 1.33 (d,
J ) 1.7 Hz, 3H).
-Eth yl-4,6-d im eth yla n ilin e (11). To a solution of 10 (170
6
) δ 6.74 (d, J ) 1.4
with Sitaxsentan Sodium, an Orally Active ET
A
Receptor
Antagonist. Pulm. Pharmacol. Ther. 2000, 13, 87-89.
4) Givertz, M. M.; Colucci, W. S.; LeJ emtel, T. H.; Gottlieb, S. S.;
Hare, J . M.; Slawsky, M. T.; Leier, C. V.; Loh, E.; Nicklas, J .
M.; Lewis, B. E. Acute Endothelin A Receptor Blockade Causes
Selective Pulmonary Vasodilation in Patients with Chronic
Heart Failure. Circulation 2000, 101 (25), 2922-2927.
4
2
mg, 1.04 mmol) in TFA (15 mL) was added triethylsilane (528
mg, 4.46 mmol). The mixture was heated under reflux over-
night before poured into ice. After basification with sodium
bicarbonate to pH 8-9, the aqueous mixture was extracted
with EtOAc. The organic layer was separated and dried
(5) Wu, C.; Decker, E. R.; Blok, N.; Bui, H.; Chen, Q.; Raju, B.;
Bourgoyne, A. R.; Knowles, V.; Biediger, R. J .; Market, R. V.;
Lin, S.; Dupr e´ , B.; Kogan, T. P.; Holland, G. W.; Brock, T. A.;
Dixon, R. A. F. Endothelin Antagonists: Substituted Mesityl
A
Carboxamides with High Potency and Selectivity for ET -
(MgSO
4
), the solids were filtered, and the filtrate was concen-
Receptors. J . Med. Chem. 1999, 42 (22), 4485-4499.
trated on rotavap to afford 11 (126 mg, ∼80% yield) as a
(6) Wu, C. Recent Discovery and Development of Endothelin Recep-
1
tor Antagonists. Expert Opin. Ther. Pat. 2000, 10 (11), 1653-
solid: H NMR (DMSO-d
6
) δ 6.62 (br s, 2H), 4.23 (br s, 2H),
1
668.
2
7
.44 (q, J ) 7.4 Hz, 2H), 2.12 (s, 3H), 2.06 (s, 3H), 1.13 (t, J )
.4 Hz, 3H).
(
7) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J .
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