Major New Drugs Creation
Chinese Pharmaceutical Journal,Vol 52,No. 01
【Abstract】 Objective: To identify the structure of the seven related substances Imp-A–G in the new drug, Aituomode, for psoriasis. Methods: HPLC-QTrap-MS and HPLCQTOF-MS were used respectively to determine the structure, and the relative molecular mass and molecular organization of the seven related substances. Results: The structures and relative molecular mass of the related substances in Aituomode were identified. Conclusion: The method is simple and accurate, providing a good idea for the identification of the related substances in bulk drugs. The experimental data obtained are valuable for researching into the related substances in Aituomode and controlling drug quality.
Chinese Journal of Medicinal Chemistry,Vol 28,No. 05
【Abstract】 Palbociclib is an orally available cyclin dependent kinase (CDK) 4/6 inhibitor. The 4-chloro-2-methylthiopyrimidine-5-carboxylate ( 2) was substituted, reduced, oxidized to give N-cyclopentyl-4-amino-2-methylthiopyrimidine-5-ethanone ( 6). Compound 6 was subjected to Wittig reaction to give 2-thiomethyl-8-cyclopentyl-5-methylpyrido[2,3- d]pyrimidine-7(8 H)-one ( 7). Compound 7 was brominated and oxidized to give 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3- d]pyrimidin-7(8 H)-one ( 8). Compound 8 reacted with tert-butyl 4-(6-amino-3-pyridyl)piperazine-1-formate to give tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate ( 9). Compound 9 transformed to tert-butyl 4-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate ( 10) by Heck reaction. Compound 10 was acidified to give palbociclib. The improved route quenched the reaction with ethyl acetate and methanol ( V: V = 1:1) giving a filtrate that simplified the workup operations. Activated manganese dioxide was used to replace 4-methylmorpholine N-oxide, which reduced the costs. Under acidic conditions, N-bromosuccinimide (NBS) was used to perform oxidation and bromination in one step. The total yield of improved route was 20.6% (based on compound 2, the total yield in the Literature  was 4.8%).
Acta Pharmaceutica Sinica,Vol 54,No. 07
【Abstract】 Alzheimer’s disease (AD) is a neurodegenerative disease that seriously threatens the life of the elderly and there is no effective therapy to treat or delay the onset of this disease. Due to the multifactorial etiology of this disease, the multi-target-directed ligand (MTDL) approach is an innovative and promising method in search for new drugs against AD. In order to find potential multi-target anti-AD drugs through reposition of current drugs, the database of global drugs on market were mined by an anti-AD multi-target prediction platform established in our laboratory. As a result, inositol nicotinate, cyproheptadine, curcumin, rosiglitazone, demecarium, oxybenzone, agomelatine, codeine, imipramine, dyclonine, melatonin, perospirone, and bufexamac were predicted to act on at least one anti-AD drug target yet act against AD through various mechanisms. The compound–target network was built using the Cytoscape. The prediction was validated by molecular docking between agomelatine and its multiple targets, including ADORA2 A, ACHE, BACE1, PTGS2, MAOB, SIGMAR1 and ESR1. Agomelatine was shown to be able to act on all the targets above. In conclusion, the potential drugs for anti-AD therapy in the database for global drugs on market were partially uncovered using machine learning, network pharmacology, and molecular docking methods. This study provides important information for drug reposition in anti-AD therapy.