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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H22N2O6
Molecular Weight 410.4199
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DARUSENTAN

SMILES

COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C2=CC=CC=C2)C3=CC=CC=C3)=N1

InChI

InChIKey=FEJVSJIALLTFRP-LJQANCHMSA-N
InChI=1S/C22H22N2O6/c1-27-17-14-18(28-2)24-21(23-17)30-19(20(25)26)22(29-3,15-10-6-4-7-11-15)16-12-8-5-9-13-16/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1

HIDE SMILES / InChI

Description

Darusentan is an orally active, propanoic acid-based endothelin receptor antagonist (ERA) that selectively blocks endothelin-1 (ET-1) binding to the endothelin type-A (ETA) receptor. Darusentan exhibited subnanomolar binding affinity and approximately 1000-fold selectivity for the ETA receptor in binding experiments conducted in vitro under steady-state conditions. Darusentan is orally bioavailable and, when administered to humans, maximum plasma concentrations are observed within 1–2 h post dosing. The mean elimination half-life is relatively long (>15 h), which is consistent with once-daily dosing. Darusentan is primarily glucuronidated by Phase II enzymes in the liver, and the major route of elimination of Darusentan and its metabolites is via the bile. Some glucuronidated metabolites of Darusentan are also excreted in the urine. Darusentan doses up to 300 mg/day were well tolerated and associated with a manageable safety profile in patients with resistant hypertension (RHTN). The most frequently reported adverse events in Ddarusentan-treated subjects were peripheral edema (17%) and headache (11%), which were mostly mild or moderate in severity. Other commonly reported adverse events in the Darusentan treatment group were sinusitis (8%), dizziness (7%), upper respiratory tract infection (5%) and gastroenteritis (5%). In phase III clinical trial the mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg with placebo, 17/10 mm Hg with Darusentan 50 mg, 18/10 mm Hg with Darusentan 100 mg, and 18/11 mm Hg with Darusentan 300 mg. Unfortunately, phase III clinical trial evaluating Darusentan did not achieve its co-primary efficacy endpoints of achieving a change in systolic and diastolic blood pressure after 14 weeks compared to a placebo. Perhaps for this reason, shortly after the top-line results of this study became known, the sponsor announced that Darusentan would not be developed further for resistant hypertension.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.8 nM [IC50]
16.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown
Primary
Unknown

Doses

AEs

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
10, 50, 100, 150, and 300 mg once daily for 10 weeks
Route of Administration: Oral
In Vitro Use Guide
The binding studies were performed using CHO cells stably expressing human ETA or ETB receptors. Membrane protein (10-50 µg) was incubated for 30 min at 25 °C in 50 mM Tris-HCl, pH 7.4, containing 5 mM MnCl2, 40 µg/mL bacitracin, and 0.2% BSA, with 25 pM [125I]ET-1 (ETA assay) or 25 pM [125I]ET-3 (ETB assay) in the presence or absence of the Darusentan. Nonspecific binding was measured with 0.1 µM ET-1.