1402837-22-2

Upstream product

• 1402838-89-4 rac-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone 
• 96797-15-8 N-trityl-4⁽⁵⁾-iodoimidazole 
• 40138-16-7 2-formylbenzene boronic acid 
• 1402838-08-7 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]benzaldehyde 
• 4630-82-4 methyl cyclohexylcarboxylate 

Relevant academic research and scientific papers

Discovery of clinical candidate (1 R,4 r)-4-((R)-2-((S)-6-Fluoro-5 H-imidazo[5,1-A[isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1

A novel class of 5-substituted 5H-imidazo[5,1-a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo[5,1-a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.

Chiral resolution, absolute configuration determination, and stereo-activity relationship study of IDO1 inhibitor NLG919

NLG919 (1) with two chiral carbon atoms on its chemical structure is a potent indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. We developed an effective way to prepare all stereoisomers of 1, the key step being the chiral resolution of racemic intermediate 2. The optimal resolution solvent system was identified as dichloromethane and n-pentane or petroleum ether. Using (?)-di-p-toluoyl-D-tartaric acid as resolution reagent, optical pure (R)-2 (e.e. > 99%, yield = 70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of 1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory activity was assessed by pharmacological experiments in vitro and in mouse, demonstrating that S configuration of C5 played an important role on the inhibition of IDO1, while the stereochemistry on C2′ exerted little effect on the IDO1 inhibitory activity in mouse.