N-3-Isoxazolyl Biphenylsulfonamides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 179
blockade in a transgenic, angiotensin II-dependent, rat model.
Hypertension 2000, 35 (4), 992-997
pressor response. Irbesartan (30 µmol/kg) and compound 7 (30
µmol/kg) were given by oral gavage (po), and the rats were
re-challenged with Ang II at various intervals up to 240 min.
There were 6-8 rats per drug dose. The difference between
the maximum blood pressure increase before and after drug
was reported as the percent (%) inhibition of the Ang II pressor
effect.
Endothelin. This study was performed as previously de-
scribed.7 Intravenous injection of big endothelin-1 (bET-1, 1.0
nmol/kg) into conscious normotensive rats causes a gradual
and sustained increase in blood pressure that is inhibited by
ETA receptor antagonists. The initial ET-1 challenge was
preceded by vehicle administration to establish a control
response to the agonist. Compounds 2 (30 µmol/kg) and 7 (30
µmol/kg) were administered iv or po after control bigET-1
pressor response at various times after drug dosing. There
were 6-8 rats per group.
Blood Pressure Measurements in Normal Telemeter-
ized SHR. Male SHR (15 weeks old; Taconic Farms) were
prepared for telemetry measurements of blood pressure and
heart rate (Data Sciences International) as described previ-
ously.14 Three groups of SHR were orally dosed with either
vehicle, irbesartan, and compound 7 (9-11 rats per group).
SHR received 1, 3, 10, 30, and 100 µmol/kg/day of irbesartan
or compound 7 for 7 days at each dose for a total of 35 days of
treatment. Blood pressure and heart rate were continuously
monitored for the 35-day period. Blood pressure and heart rate
differences between groups were tested with a linear model
using SAS PROC MIXED, and Hochbergs’s step-up procedure
was applied to compensate for the multiple comparisons.
Caco-2 Cell Permeability Assay. This study was per-
formed as previously described.16
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(9) Murugesan, N.; Gu, Z.; Spergel, S.; Young, M.; Chen, P.; Mathur,
A.; Leith, L.; Hermsmeier, M.; Liu, E. C.-K.; Zhang, R.; Bird,
E.; Waldron, T.; Marino, A.; Koplowitz, B.; Humphreys, W. G.;
Chong, S.; Morrison, R. A.; Webb, M. L.; Moreland, S.; Trippodo,
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Antagonists. 4. Discovery of N-[[2′-[[(4,5-Dimethyl-3-isoxazolyl)-
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Supporting Information Available: Results from el-
emental analysis. This material is available free of charge via
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