660449-06-9

Upstream product

• 4294-57-9 para-methylphenylmagnesium bromide 
• 394-31-0 2-amino-5-hydroxybenzoic acid 
• 64373-43-9 5-methyl-3-oxo-hexanenitrile 
• 556-24-1 methyl 3-methylbutanoate 
• 214957-87-6 N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide 
• 660448-80-6 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide 
• 660448-79-3 benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[methoxy(methyl)amino]carbonyl}phenyl)carbamate 
• 214957-88-7 2-{[(benzyloxy)carbonyl]amino}-5-hydroxybenzoic acid 
• 1330529-96-8 (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(4-methylphenyl)methanone 
• 660449-04-7 tert-butyl {[6-hydroxy-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-3-yl]methyl}carbamate 
• 660449-03-6 6-hydroxy-4-(4-methylphenyl)-2-(2-methylpropyl)quinoline-3-carbonitrile 

Downstream Products

• 660449-07-0 tert-butyl ({6-[2-(methylamino)-2-oxoethoxy]-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-3-yl}methyl)carbamate 

Relevant academic research and scientific papers

Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554

We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1′ pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.

Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554

Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl] piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC50 = 1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.