Design and synthesis of novel NM-3 antiangiogenic analogues with increased potency and reduced protein binding

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NM-3 [3-(2-methylcarboxymethyl)-6-methoxy-isocoumarin] is an orally active anti-angiogenic agent that has been evaluated in Phase I clinical trials in the U.S. and France. NM-3 has been demonstrated to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC), suppress the secretion of vascular endothelial growth factor (VEGF) expression and inhibit xenograft tumor growth alone and to enhance anti-tumor effects of standard chemotherapy and radiotherapy without noticeable toxicity. Administration of NM-3 to humans has been well tolerated up to doses of 4.7 g/m²/day without any significant dose limiting toxicities (DLTs). Stable disease has been reported in the Phase I studies. Although there is good oral linear bioavailability up to 1 g/m² with plasma levels reaching 144 ug/mL, NM-3 was shown to be tightly bound to serum albumin, which may limit its exposure and activity in man. A number of analogues have been synthesized and evaluated in antiangiogenic models for activity and affinity for protein binding. Three compounds have been selected for further evaluation which demonstrate more than 5 fold enhanced antiangiogenic activity and 20% reduced affinity for albumin binding compared to NM-3. Structure activity relationships will be provided. One of these new compounds will potentially be selected for development, which may provide for more significant exposure and in vivo antitumor activity.