CP 673451

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Description

CP 673451 is a pharmacologically selective PDGFR-beta inhibitor and PDGF-BB-stimulated autophosphorylation of PDGFR-beta in cells (IC50 = 1 nmol/L) being more than 450-fold selective for PDGFR-beta versus other angiogenic receptors. Inhibition of PDGFR-beta phosphorylation in tumors correlates with plasma and tumor levels of CP673451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC50 of 120 ng/mL in plasma at C(max). In a sponge angiogenesis model, CP 673451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. x 5, p.o., corresponding to 5.5 ng/mL at C(max)). In vivo, CP 673451 inhibits tumor PDGFR-beta phosphorylation, and it also selectively inhibits PDGF-BB-stimulated angiogenesis. CP 673451 causes significant tumor growth inhibition in multiple human xenograft models.

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