Me-too Drug Design, Synthesis And Kinase Activity Research Based On The Pazopanib

Me-too drug development is a kind of follow-up drug discovery strategy which can quickly obtain the strong activity and low toxicity candidate drug molecules that come from structure modification of clinical phase III stage or marketed drugs, called lead compounds. Compared with pioneering innovative drug development, it is a less difficult and risky but more successful way, and is regarded to be adaptive to the Chinese conditions. Pazopanib (Votrient(?), made by GlaxoSmithKline), a representative anti-angiogenesis drug, has been approved by FDA for the treatment of patients with advanced renal cell carcinoma and soft tissue sarcoma. In spite of the advantages in multi-targets and good oral bioavailability, Pazopanib showed some toxity and side effects in clinic trial, especially highlighted in hepatotoxicity. In order to obtain novel derivatives of Pazopanib with better efficacy and lower side effects, we designed two types of novel cycloalkyl[d]pyrimidine skeletons derived from the pyrimidine linker in Pazopanib, under the premise of employing as small as possible changes. A total of33derivatives (A01-A22and B01-B11) containing these two skeletons (6,7-dihydro-5H-cyclopenta[D]pyrimidine and5,6,7,8-tetrahydroquinazoline) were synthesized, and two more intermediates (C01and D01) were synthesized for facilitating the summary of SARs. All35derivatives were tested in four pro-angiogenic kinase inhibitory or activation assays (PDGFR-P, VEGFR-2, c-Kit and FGFR-1). The results indicated that6derivatives showed moderate inhibitory activities against PDGFR-β(10μM<IC50<5O μM),5derivatives showed moderate inhibitory activities against VEGFR-2(10μM<IC50<40μM),3derivatives showed moderate inhibitory activities against c-Kit (10μM<IC50<30μM), and4derivatives showed moderate inhibitory activities against FGFR-1(10μM<IC50<50μM). It is noteworthy that derivatives A01and B02showed, to a certain degree (decrease40-1000times than that of Pazopanib), quadruple-target kinase inhibitory properties. Considering the novelty and similar structure compared with Pazopanib. these two derivatives may serve as a reasonable lead compound for further developments. Our research identified accidentally that19derivatives showed good activation effects on FGFR-1(1μM<EC50<10μM),3derivatives showed potent activation effects on FGFR-1(EC5O<1μM), including2derivatives with very potent activation effects (EC50<0.1μM). On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of these35derivatives, which give some valuable clues for further design and development of me-too anti-cancer drug of Pazopanib. To our knowledge, these activators are the first-in-class small molecular FGFR-1agonists, which might be used as an effective chemical biology tool for the study of FGFR-1-related signaling pathway.