Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia.

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM).

The phosphoinositide-specific phospholipase C inhibitor U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) spontaneously forms conjugates with common components of cell culture medium.

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in the regulation of Ca(2+) release from inositol 1,4,5-triphosphate-sensitive stores. U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) has been extensively used as a pharmacological inhibitor of PLC to elucidate the importance of this enzyme family in signal transduction pathways. U73122 has an electrophilic maleimide group, which readily reacts with nucleophiles such as thiols and amines.

Conformation analyses, dynamic behavior, and amide bond distortions of medium-sized heterocycles. 2. Partially and fully reduced 1-benzazocines, benzazonines, and benzazecines.

Partially and fully reduced forms of benzo-fused eight- to ten-membered nitrogen heterocycles (1-benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features, transannular distances and dynamic behavior were studied using X-ray crystallography and VT NMR spectroscopy. The amide moiety in the nine-membered benzazonine ring 5b favors N-pyramidization, whereas the ten-membered benzazecine 5c adopts an amide twist.

Conformation analyses, dynamic behavior and amide bond distortions of medium-sized heterocycles. 1. Partially and fully reduced 1-benzazepines.

Five 1-benzazepine heterocycles were synthesized by utilizing transition-metal-catalyzed processes in key bond-forming steps. exo-Methylene and methyl substituents were introduced at position 5, as well as a unit of unsaturation between positions 3 and 4, with benzoyl or benzyl N-substituents. Solution- and solid-state structures were examined, using dynamic NMR spectroscopy and X-ray crystallography, corroborated by molecular mechanics calculations.