Design, Synthesis And Activity Of Novel Indoleamine-2,3-Dioxygenase 1 (IDO1) Inhibitors

Cancer is the most deadly disease of human being with increasing morbidity and lethality in recent years.It has gotten some achievements in fighting against cancer through four stages:operative treatment,chemotherapy,radiotherapy and targeted therapy.With the development of immundogy,the tumor immunotherapy of self-immune system has become the new focus of cancer treatment.Cancer immunotherapy has been nominated for the‘Year Breakthrough of Cancer Research 2013'by Science magazine.Indoleamine 2,3-dioxygenase1,?later referred to as IDO1?is the rate limiting and initial step of kynurenine pathway.Clinical studies indicated that IDO1 is silent in most tissues but highly active in many types of cancer cells.it is a potential new target of tumor immunity treatment.So researching IDO1inhibitor is very important to tumor immunity treatment.Researchers have reported some IDO1 molecular inhibitors by the method of modificating natural products,high throughput screening,structure-based design.However,at present,there are only two molecular inhibitors?Epacadostat and NLG919?in clinical research,and still has not effective IDO1 inhibitors on market.At present,IDO1 inhibitors,the most of them either showed low potency,be failed in vivo assay.IDO1 inhibitors might be useful in combination with traditional chemotherapeutil,drugs or therapeutic cancer vaccines.Thus,researching IDO1 small-molecule inhibitors with high-activity and specificity as the candidate drug of targeted is an important work to tumor immunity treatment.This article basing on using the valuable structural information revealed by co-crystal structures of IDO1 with its ligands,through combining the disadvantages of patent medicine of existing IDO1 inhibitors and utilizing the method of designing the reasonable medicine with computer,designs five series of compound of various skeletons:substituent groups at9-position of 9H-pyrido[3,4-b]indole,substituent groups at 4-position of 1H-pyrazolo[3,4-d]pyrimidin-4-amine,substituent groups at 4-position of 1H-indazol-4-amine,substituent groups at 3-position of?1H-pyrazol-4-yl?pyridine,substituent groups at?of 5-aminonicotinamide and 3-aminoisonicotinamide.The core ideas of this design including:?1?an atom with a free electron pair that can coordinate to the Fe iron?ligands not obeying this rule generally show low inhibitory activities?;?2?The ligands occupied pocket A or pocket B,or occupied both pocket A and pocket B,which may obtain better inhibitory activities;?3?groups in larger ligands that can form hydrogen bond to Ser167,Gly262,Ala264,and Arg231 or to the heme 7-propionate.Then,after effectively creating four varieties of thirty compounds which were mentioned in foregoing paleography,and through the enzyme activity screening,we find1H-indazole derivatives compounds with well IDO1 inhibitors activity for the first time,and the fixing to optimize these substituent groups at both 4-position and 6-position,by increasing the structural diversity of the substituent groups at the 4-position,in order to more preorganize for binding to IDO1.For binding to IDO1,we created about twenty compounds,and finished the enzyme activity screening.A series of new 1H indazole derivatives were synthesized and determined the enzyme inhibitory activities,and the compound V-1p exhibited the highest activity,with an IC₅₀ value of 5.3?M.Finally,through testing enzyme inhibitory activities,and the technology of molecular docking,we report the structure-activity relationships?SARs?analysis of the 1H-indazole derivatives as novel IDO1 inhibitors...