JNJ-10198409, also known as RWJ 540973, is a potent inhibitor of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK).
JNJ-10198409 has anti-PDGFR-β kinase activity with an IC50 of 4.2 nM and potent antiproliferative activity in six of eight human tumor cell lines, with IC50 values of less than 33 nM. Ho, C.Y., et al. "(6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells." J. Med. Chem. 48: 8163-8173 (2005).
The in vivo inhibitory effect of JNJ-10198409 on PDGF-RTK was confirmed in tumor tissues after administering the compound orally in a nude mouse xenograft model of human LoVo colon cancer. DAndrea, M.R., et al. "Validation of in vivo pharmacodynamic activity of a novel PDGF receptor tyrosine kinase inhibitor using immunohistochemistry and quantitative image analysis." Mol. Cancer Ther. 4: 1198-1204 (2005).
Multiple UDP-glucuronosyltransferase 1A enzymes are responsible for the glucuronidation of JNJ-10198409 in human liver microsomes. Yan, Z., et al. "N-glucuronidation of the platelet-derived growth factor receptor tyrosine kinase inhibitor 6,7-(dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine by human UDP-glucuronosyltransferases." Drug Metab Dispos 34: 748-755 (2006).
JNJ-10198409 demonstrated potent anti-proliferative activities against human leukemia cells K562 and SUP-B15. It induced cell apoptosis concentration-dependently while the remaining viable cells demonstrated G2/M cell cycle arrest. Using K562 growing as a solid tumor in nude mice, JNJ-10198409 caused dose-dependent inhibition of tumor growth without overt toxicity in vivo. Mei, J., et al. "A novel PDGFR kinase, c-ABL and c-Kit inhibitor with unique anti-proliferative activity inducing specific cell cycle dysregulation in human leukemia cells " Proc. Amer. Assoc. Cancer Res. 45: Abstract #5982 (2005).
JNJ-10198409 has both anti-angiogenesis and tumor cell anti-proliferative activities. Mei, J., et al. "A novel PDGF receptor tyrosine kinase inhibitor with dual anti-angiogenesis and tumor cell anti-proliferative activity." Proc. Amer. Assoc. Cancer Res. 45: Abstract #3990 (2004). Tuman R., et al. "Discovery of a novel, dual mechanism anti-angiogenic and anti-proliferative agent with oral anti-tumor activity." Proc. Amer. Assoc. Cancer Res. 45: Abstract #4558 (2004).
JNJ-10198409 selectively inhibited neuroblastoma cell growth in alamarBlue® assays and rapidly induced neuroblastoma cell apoptosis without affecting the growth of primary pediatric neural crest-like stem cells. It may function by inhibiting the activity of Src family kinases. Fujitani, M., et al. "Potent and selective cytotoxic and cytostatic activity of JNJ-10198409 against neuroblastoma cells." Chiba Medical J. 88E: 27-34 (2012).
As of October 2012, it appears that Chemical Abstracts Service is erroneously using the name "JNJ-10198409" for CAS number 627512-69-0. The structure that Chemical Abstracts Service shows for CAS number 627512-69-0 is actually a double-bond tautomer of JNJ-10198409, according to J. Med. Chem. 48: 8163-8173 (2005). This is the publication that describes the discovery of JNJ-10198409 and in which the CAS number 627518-40-5 is specifically assigned to the correct structure for JNJ-10198409. Thus, it appears that the correct CAS number for the correct structure is 627518-40-5, as appears near the top of this product entry.
Another CAS number previously assigned to this product, namely 872872-33-8 has been deleted by CAS and is no longer in use.
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This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.
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