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Updated: Aug 15, 2026
An Immature Murine Model of Reversible Unilateral Ureteral Obstruction
Published on: April 4, 2025
Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse
Guohua Zhao1, James John Mignone1, Leatte Guernon1
1Bristol Myers Squibb Research & Development , P.O. Box 4000, Princeton, New Jersey08543, United States.
Abstract:
Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2-5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αVβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αVβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αVβ1, αVβ3, αVβ5, and αVβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total collagen by 25% versus vehicle.
Insights
New pan-αV integrin inhibitor compound 14 shows promise for treating fibrotic diseases like idiopathic pulmonary fibrosis (IPF) and kidney fibrosis by reducing collagen levels.
Area of Science:
- Pharmacology
- Integrin Biology
- Fibrotic Disease Research
Background:
- Fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis, represent a significant unmet medical need with limited therapeutic options.
- Current treatments for IPF offer minimal efficacy and poor tolerability, highlighting the urgent requirement for novel therapeutic strategies.
Purpose of the Study:
- To develop novel pan-αV integrin inhibitors with oral pharmacokinetics and selectivity over αVβ8 and αIIbβ3.
- To identify a potent and orally bioavailable inhibitor for potential treatment of fibrotic conditions.
Main Methods:
- Lead optimization was employed to identify compound 14, a selective inhibitor targeting αVβ1, αVβ3, αVβ5, and αVβ6 integrins.
- Preclinical efficacy was assessed using a mouse unilateral ureteral obstruction model of kidney fibrosis.
Main Results:
- Compound 14 demonstrated potent inhibition of αVβ1, αVβ3, αVβ5, and αVβ6 integrins with high selectivity.
- Oral administration of compound 14 (10 mg/kg/day for 8 days) in a mouse model significantly reduced total collagen by 25% compared to vehicle treatment.
- The compound exhibited favorable pharmacokinetic properties, including oral bioavailability and low intravenous clearance.
Conclusions:
- Compound 14 represents a promising therapeutic candidate for fibrotic diseases due to its potent and selective αV integrin inhibition and demonstrated efficacy in a preclinical model.
- The development of orally available pan-αV integrin inhibitors offers a potential new avenue for treating debilitating fibrotic conditions.
