Reduced eosinophil infiltration and bronchial hyperreactivity has been shown with antibodies and small molecules targeting VLA-4 receptor by parenteral or intratracheal route. We describe the PK/PD profile of UR-13484, a novel orally active small molecule VLA-4 antagonist.
UR-13484 inhibits VLA-4-dependent cell adhesion to CS-1 fragment and VCAM-1 (IC50=78 nM and 2.1 μM, respectively). It is selective vs. VLA-5 (IC50>10 μM) but not for α4β7 (IC50=1-10μM). It also inhibits T lymphocyte proliferation induced by VCAM-1/OKT3 (IC50=2.7 μM). It shows medium permeability in Caco-2 cells (Papp»6x10-6 cm/sec), good stability in human microsomes and hepatocytes (33% and 36% disapp. at 1 h), low CYP inhibition (IC50 for 3A4, 2D6 and 2C9 > 10 μM), and acceptable protein binding (92%). Oral PK/PD profile in rats shows a short t1/2 (about 30 min), but an extended duration of action (up to 4 h) as demonstrated by the increase in WBC count. In vivo activity was studied in OVA-sensitized Brown Norway rats. Treated animals received UR-13484 at 30 mg/kg, 1 h before and 4 h after OVA challenge. Total cell and eosinophil counts in BAL were reduced in treated rats (52% and 58% reduction respectively, p<0.05). The increase in bronchial hyperreactivity (RL) to 5-HT was practically abolished with this treatment.
In conclusion, the blockade of VLA-4 with orally active small molecules, such as UR-13484, may represent a good strategy for the treatment of asthma.