Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 ([7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active N-Oxide Metabolite TG100855 ([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine)

Abstract

TG100855 is 2 to 9 times more potent than the parent compound. Flavin-containing monooxygenases are the primary enzymes mediating the biotransformation. Significant conversion of TG100435 to TG100855 has been observed in rat and dog after oral administration. Systemic exposure of TG100855 is 1.1-and 2.1-fold greater than that of TG100435 in rat and dog after oral dosing of TG100435. Since TG100435 is predominantly converted to the more potent N-oxide metabolite across species in vivo and in vitro, the overall tyrosine kinase inhibition in animal models may be substantially increased after oral administration of TG100435.The Src kinase family consists of a group of nonreceptor protein tyrosine kinases (PTKs) including Src, Yes, Fyn, Lyn, Hck, Blk, Brk, Fgr, Frk, Srm, Lck, and Yrk (Trevino et al., 2006). Src PTKs play critical roles in a variety of cellular signal transduction pathways regulating diverse processes including cell survival, proliferation, motility, adhesion, and transformation. Elevated or constitutive activation of Src kinase is commonly observed in tumors, most notably in colon and breast cancer, but also occurs in other tumor types, including pancreatic cancer (Lutz et al., 1998). Overexpression of Src PTKs has been associated with tumorigenesis, metastasis, and invasion; consequently, Src family kinases have become very important biological targets in oncological drug development. Small molecule kinase inhibitors have shown great promise as a new class of therapeutics. Most small molecule kinase inhibitors bind at the ATP-binding site and exhibit much less toxicity than currently used chemotherapeutic agents (Levitzki and Mishani, 2006).Nitrogen-containing small molecules are the most common of all of the organic compounds of pharmacological interest. The functionalities of nitrogen provide flexibility in the drug design toward proper potencies and physical properties. However, the multiple oxidation states of nitrogen increase the metabolic instability of drug candidates (Cho and Lindeke, 1988). N-Oxidation is a common biotransformation of aliphatic tertiary amine-containing compounds. The pharmacological and toxicological importance of this metabolic pathway has been widely studied. The nitrogen-centered oxidation of tertiary amine drugs is commonly considered as a detoxification pathway resulting in nontoxic and biologically inactive metabolites (Carmella et al., 1997;Cashman and Zhang, 2006;Krueger et al., 2006). The benign nature of tertiary amine N-oxides under normal physiological conditions has been used as a prodrug approach to selectively elicit cytotoxic events associated with hypoxic conditions in solid tumor

Non‐Aqueous Phospholipid Concentrates for Increasing the Bioavailability of Poorly Soluble Compounds

“…achieved an improved bioavailability for the tumour‐inhibiting Src (sarcoma) kinase inhibitor TG100435 and its metabolite TG 100855 (TargeGen Inc., San Diego, USA) by the application of PHOSAL 50 PG in rats and dogs. [ 18 ] The formulation of the active ingredient in PHOSAL 50 PG showed the best area under the curve (AUC) values for dosages of 25 and 100 mg kg −1 in comparison with the other formulations using aqueous methylcellulose, aqueous Lutrol F‐68 (polyoxypropylene‐polyoxyethylene block co‐polymer) and aqueous Solutol HS15 (12‐hydroxystearic acid‐polyethylene glycol co‐polymer), which was explained by an improved solubility of the active ingredient in the lipidic phase.…”

N‐(2,4)‐dinitrophenyl‐L‐arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator

“…Therefore, treatment with a chemical compound with EphB4‐activating properties represents a very appealing option. While several small‐molecule inhibitors of the EphB4 kinase activity have been described , a small molecular weight EphB4 activator has yet to be reported. While kinase activation for therapeutic purposes still represents a novel concept, previous overall success in targeting tyrosine kinases suggests that this approach should most likely be treatment relevant.…”