Design,Synthesis And Anti-inflammatory Activity Evaluation Of GRPR Inhibitors Based On RH-1402 Structure

Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the synovial membrane.It is characterized by long duration,poor prognosis,and difficult treatment.The activation of gastrin-releasing peptide receptors not only mediates the signal transduction of pruritus and promotes the development of tumorigenesis,but also has a large number of immunological effects that can promote the development of inflammatory diseases,suggesting that blockade of GPRP signal transduction can be used as a An effective way to treat inflammatory diseases.Our group has reported a class of GRPR small molecule inhibitors with anti-itching activity.In this paper,the GRPR inhibitor RH-1402 with the best anti-itching activity was first evaluated in a rat model of rheumatoid arthritis to obtain pharmacodynamic data.As a basis for designing small molecule inhibitors of GRPR with anti-inflammatory activity,a class of inhibitors of GRPR with anti-inflammatory activity was designed.In this paper,we first searched the protein database through blast and determined that 1u19 protein was used as a template to predict the GRPR tertiary structure.Using MOE molecular simulation software,the small molecule and target were docked to score 28 new compounds.These 28 new compounds were synthesized by bioactive natural products such as cinnamic acid,benzoic acid,and phenylacetic acid.Natural amino acids such as L-phenylalanine,L-tyrosine,L-tryptophan and glycine were used as the linker.In part,linked to the drug fragment2-(1H-imidazol-1-yl)ethanamine or 2-(1H-morpholin-1-yl)ethanamine,using EDCI/Ho Bt to catalyze the formation of an amide bond between a carboxyl group and an amine group.The target compound was purified by recrystallization method.The structure of the target compound was characterized by 1H-NMR and TOF-HRMS,and the melting point of the target compound was tested.In this paper,a green and rapid preparation method was proposed to synthesize2-(1H-imidazolyl)ethylamine.Using imidazole and acrylamide as raw materials,2-(1H-imidazol-1-yl)b was obtained through Michael addition and Hoffman degradation.Amine,the total yield can reach 78%.Finally,the LPS-stimulated RAW264.7 inflammatory cell model was used to screen the anti-inflammatory activity of the target compound and the possible structure-activity relationship was inferred.The anti-inflammatory activity of 28 new compounds and RH-1402 was evaluated using the content of NO,TNF-?,and IL-1?in the inflammatory mediators in the cell supernatant.Gradient experiments wereperformed on compounds with obvious anti-inflammatory activity.This indicates that these compounds with significant anti-inflammatory activity have a dose-dependent protective effect on LPS-stimulated RAW264.7 inflammatory cells.