Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse...

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.