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NIH grant 1R43DK143871-01A1: Discovery of a Novel V1aR Partial Agonist
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Glenn E Croston. Award: $449987.
Start: 2026-09-11T00:00:00.
In liver cirrhosis patients, refractory ascites is a common complication affecting 40,000-50,000
patients at any given time. Cirrhosis causes imbalances in blood pressure, namely elevated
pressure in the portal vein and decreases in arterial pressure leading to accumulation of fluid
in the abdomen due to increased blood flow through the small intestine, refractory ascites,
with associated morbidity, including a high risk of failure of renal and hepatic function, and a
1-year mortality rate of 50%. There are no approved drugs for refractory ascites, with
treatment restricted to frequent paracentesis to remove ascites fluid from the abdomen, or
surgical options, all with significant risks for patients and high costs. Other drugs targeting
V1aR are limited by clear liabilities. An older drug, terlipressin, demonstrates that agonism at
the V1a receptor, highly expressed in mesenteric arteries, can partially fix the pressure
imbalances of portal hypertension and refractory ascites by reducing blood flow into the portal
vein. While validated clinically, V1aR full agonism by the prodrug terlipressin carries a
significant risk of excessive vasoconstriction and associated tissue ischemia. Building upon
previously published work, a bifunctional partial V1a agonist will be discovered. This new
molecule should be suitable for outpatient, SC administration. If successful, this would be the
first drug suitable for directly treating refractory ascites providing a significant improvement in
care for these patients.
Specific aims to achieve this goal include (SA1) synthesis and in vitro testing of V1aR partial
agonist peptides with acceptable PK following SC delivery (SA2), and pharmacodynamic
confirmation of V1aR partial agonist impact on arterial pressure and portal pressure (SA3).
With these aims and milestones, the company will be positioned for a Phase 2 SBIR
application, development of novel composition of matter IP, and be in position to deliver an
important new therapeutic for refractory ascites patients, a group who remains urgently in
need of new therapeutic approaches.document fetched 2026-09-20 02:42