Vicriviroc Malate

In order to determine if vicriviroc malate is a receptor agonist or antagonist, three functional assays were employed to measure the ability of the compound to block b-chemokine signaling in CCR5-expressing cells.A chemotaxis assay was first employed to determine the ability of vicriviroc malate to inhibit chemokine-mediated migration of a mouse Ba/F3 cell line stably expressing recombinant human CCR5. In this assay, vicriviroc malate showed equally potent inhibition of the chemotactic response to MIP-1 with IC50 values below 1 nM. The ability of vicriviroc malate to inhibit intracellular calcium release induced by receptor stimulation was also assessed. A assay utilized to demonstrate the ability of vicriviroc malate to inhibit CCR5 receptor signaling was a GTPS exchange assay. GTPS binding induced by RANTES. vicriviroc malate potently inhibited RANTES-induced signaling with mean IC50s of 4.2 nM. ^[1] Vicriviroc Malate is highly water-soluble and demonstrates oral bioavailability of >89% in rats and monkeys. The compound is modestly human plasma protein-bound (≈84%) and widely distributed in the extra vascular space.Absorption and exposure in humans are linear and doseproportional, with a terminal phase half-life >24 hours supportive of once daily dosing. Variability in absorption is modest (20–40%). ^[2] Vicriviroc Malate is NOT A p-glycoprotein Substrate In Vitro. ^[3]