Discovery of triazine-benzimidazoles as selective inhibitors of mTOR

The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors

“…[11][12][13][17][18][19][20][21] We have previously reported the results of a high-throughput screening effort that identified benzimidazole-triazine 1 ( Figure 1) to be a moderately potent inhibitor of PI3K (IC 50 = 350 nM) and mTOR (IC 50 = 93 nM). 22,23 Compound 1 also showed moderate potency in the U87 MG pAKT cellular assay; however, it was metabolically unstable and showed high in vitro clearance in rat liver microsomes (CL int = 291 L/min/mg). Rat bile duct cannulation studies determined that oxidation on the benzimidazole core was one route of metabolism.…”

“…We postulated that the imidazo[1,2-a]pyridine core may provide the desired potency, efficacy, and stability and would also be amenable to the substitution patterns required for our established SAR. Therefore, this disclosure explores imidazo[1,2-a]pyridines as an alternative 5,6-heterocylic core utilizing information that has been acquired in our PI3K and mTOR 23,25 programs to discover potent and efficacious PI3K/mTOR dual inhibitors. The compounds described herein are represented by general structure 3.…”

“…Rat bile duct cannulation studies determined that oxidation on the benzimidazole core was one route of metabolism. 23 In addition to poor metabolic stability, benzimidazole-triazine 1 was not selective over protein kinases such as B-raf ( V600E B-Raf IC 50 = 3 nM). However, we believed that compound 1 was a reasonable lead as a PI3K inhibitor and, with X-ray co-crystal and modeling studies, we sought for ways to improve its potency, selectivity, and metabolic stability.…”

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

“…This compound inhibited 18 cancer cell-lines' proliferation (IC 50 <1 μM) in tissue culture experiments, HGF-stimulated Akt phosphorylation in liver at 30 mg/kg and S6RP phosphorylation at 100 mg/kg in vivo tests. Compound 14 ( Figure 5) was more than 100-fold selective over the other PI3K isotherms, furthermore, 14 was selected in order to research the selectivity of mTOR inhibitor on cancer cell lines that observed high clearance and poor exposure in vivo although the best potency/ selectivity combination [54].…”

Catalyst‐Controlled Chemoselective Arylation of 2‐Aminobenzimidazoles

“…[2d] During our work on the N-arylation of nitrogen-containing heterocycles, [3] we became interested in the use of 2-aminobenzimidazoles as potential substrates for chemoselective Narylation reactions. Both N 1 -aryl-2-aminobenzimidazoles and 2-arylaminobenzimidazoles are found in a variety of medicinally important compounds including integrin α 4 β 1 antagonists, [4] mTOR inhibitors, [5] aurora kinase inhibitors, [6] Tie-2 kinase inhibitors, [7] Ca channel blockers, [8] and CXCR2 antagonists. [9 Thus, the selective syntheses of both of these isomers from a common core structure represent attractive alternatives to other previouslyemployed routes [10][11] and could provide rapid access to a diverse array of potentially bioactive 2-aminobenzimidazole derivatives (Scheme 1).…”