Improvement by solid dispersion of the bioavailability of KRN633, a selective inhibitor of VEGF receptor-2 tyrosine kinase, and identification of its potential therapeutic window

Abstract

KRN633 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. However, it is poorly water-soluble; consequently, relatively high doses are required to achieve substantial in vivo tumor growth suppression after oral administration. We subjected KRN633 to the solid dispersion technique to improve its solubility, absorption, and antitumor efficacy after oral administration. This technique transformed the drug into an amorphous state and dramatically improved its dissolution rate. It also enhanced the bioavailability of the drug in rats by f7.5-fold. The solid dispersion form of KRN633 also dramatically inhibited human tumor growth in murine and rat xenograft models: similar rates of tumor growth inhibition were obtained with 10-to 25-fold lower doses of the solid dispersion preparation relative to the pure drug in its crystalline state. Histologic analysis of tumors treated with the solid dispersion preparation revealed a significant reduction in microvessel density at much lower doses when compared with the crystalline form preparation. In addition, a dose-finding study using the solid dispersion form in a rat xenograft model revealed that there was a substantial range of doses at which KRN633 in the solid dispersion form showed significant antitumor activity but did not induce weight loss or elevate total urinary protein levels. These data suggest that the solid dispersion technique is an effective approach for developing

KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties

“…KRN633 (19,20) showed higher IC 50 values of 7.1, 4, 14, and 15 nmol/L, respectively. Only AZD2171 (21) shows a comparable level of inhibition (IC 50 = 0.4 nmol/L).…”

“…Accordingly, it is clear that KRN951 is a highly potent VEGFR-2 tyrosine kinase inhibitor with antitumor and antiangiogenesis properties that might be applicable for the treatment of solid tumors and other diseases involving pathologic angiogenesis. Although many synthetic VEGFR-2 tyrosine kinase inhibitors have been reported (13)(14)(15)(16)(17)(18)(19)(20)(21), it is worth noting that KRN951 possesses significantly more potent in vitro and in vivo activities in comparison. KRN951 inhibited VEGF-dependent proliferation of HUVECs with an IC 50 of 0.67 nmol/L, whereas in similar assays, PTK787/ZK 222584 (13), SU11248 (14), CP-547,632 (15), and Figure 4.…”

“…In particular, bevacizumab, a recombinant humanized monoclonal antibody to VEGF, has been approved as a first-line therapy for metastatic colorectal cancer (12). In addition, several VEGFR tyrosine kinase inhibitors are currently under preclinical or clinical development (13)(14)(15)(16)(17)(18)(19)(20)(21). Recently, two small-molecule inhibitors with activities against VEGFR tyrosine kinase, BAY 43-9006 (17) and SU11248 (14), have been approved for the treatment of patients with advanced renal cell cancer.…”

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs

“…A low drug solubility, low dissolution rate and incomplete absorption after oral administration in the gastrointestinal fluids affect the therapeutic effect of poorly water-soluble drugs 3 and seriously limit their application. There are many traditional pharmaceutical solubilization methods to increase their dissolution rate, such as forming inclusion complexes with cyclodextrins 4-6 , solid dispersion technology [7][8][9] , ultra-fine grinding [10][11][12] , adding solubilizers and co-solvents 13,14 , and salt formation 15,16 . The development of nanotechnology provides a new way to solve the problem of the slow dissolution rate of poorly water-soluble drugs.…”

Synthesis and Biological Evaluation N-(6,7-dimethoxynaphthalen-yl) sulfamide Derivatives as Novel Inhibitors of Angiogenesis and Tumor Growth

“…In addition, a sequence of quinazoline derivatives with two methoxyl groups such as KRN633 and quinoline derivatives containing two methoxyl groups such as KRN951, which are more active in cell assay and reducing HUVEC growth, have been reported. Moreover, KRN633 and KRN951 reflect fine security, proved by nude mice assay [27][28][29][30][31]. Therefore, in an effort to search for small molecular entities with both anti-angiogenesis activities and conventional anticancer property for cancer treatment, we decided to design the 15 compounds with the structural features of the 9n, KRN633 and KRN951.…”