Cross border application of pyrazine

In 1879, tetramethylpyrazine was isolated from fusel oil fermented in beet and found In 1888, pyrazine was synthesized for the first time In 1928, Reichstein & slauettingar discovered pyrazine, methylpyrazine, 2,5-dimethylpyrazine and 2,6-dimethylpyrazine from coffee Pyrazine compounds began to "cross-border" the field of food flavor At present, these compounds have become a kind of heterocyclic synthetic flavor with the most members of food flavor family However, pyrazine was initially used in the field of medicine, such as anti tuberculosis, moth repellent, anticonvulsant and antibacterial agents The substructure of pyrazine was searched in the drug crossover database, and 168 drug data were obtained, including 33 drugs on the market, mainly distributed in the fields of anti-tumor and anti infection Although the total number of pyrazine drugs on the market is small, there are many new drugs in various fields in recent years, and there are some new target drugs worthy of attention In this paper, some typical pyrazine drugs were selected for introduction Export protein (xpo1) exists in the nucleus, and its main function is to recognize and combine the output signal, so as to help the substance in the nucleus export to the cytoplasm through the nuclear pore complex Xpo1 is a novel target, so far, there is only one drug on the market Selinexor was approved by the U.S Food and Drug Administration (FDA) in 2019 as an xpo1 inhibitor The drug blocks the nuclear export of tumor suppressor protein (TSPS), growth regulator and oncogen protein mRNA by blocking xpo1, resulting in the increase of intranuclear TSPS and the decrease of some oncoproteins such as c-myc and CyclinD1, so as to achieve the purpose of cell cycle arrest and tumor cell apoptosis Pulmonary hypertension is a disease characterized by the rise of pulmonary artery pressure, which often causes right ventricular failure and leads to death It is a common complication of many diseases in clinic One of the important characteristics is arterial embolism caused by vasoconstriction and platelet aggregation Selexipag, a pyrazine drug, is a prostaglandin receptor (IP receptor) agonist, which has the function of vasodilation The drug was approved by FDA in 2015 to treat pulmonary hypertension Selexipag is a prodrug, which is hydrolyzed by carboxylesterase 1 in vivo to obtain about 37 fold active metabolites Compared with other prostaglandin receptors (Ep1-4, DP, FP and TP), celecoxib and its active metabolites are selective for IP receptors The clinical trial results of 1156 patients showed that selexipag treatment resulted in a 40% reduction in the incidence of primary endpoint events compared with placebo (99% CI: 22% to 54%; bilateral log rank P < 0.0001) In March 2014, favipiravir, a pyrazine drug, was approved for marketing in Japan to treat the new type of recurrent influenza Favipiravir can selectively inhibit RNA polymerase related to influenza virus replication, which is a new antiviral drug with a new mechanism of action The drug can be phosphoribosylated by the host cell enzyme to produce fabiravir ribosyl-5 '- triphosphate inositol with biological activity The virus RNA polymerase mistakenly recognizes fabiravir RTP, inserts it into the virus RNA chain or binds with the virus RNA polymerase domain, thus hindering the replication and transcription of the virus RNA chain Smoking has always been a major global public health problem Smoking leads to a very high mortality and disability rate of diseases, especially cardiovascular diseases and cancer According to the statistics in 2007, there are more than 350 million smokers in China It is estimated that by 2030, the death toll of tumors, cardiovascular and cerebrovascular diseases and chronic respiratory diseases caused by tobacco use will reach 2 million Smoking is a variable factor in the incidence rate Therefore, smoking cessation can significantly reduce the morbidity and mortality of patients But smoking is a very difficult task for ordinary people The success rate of smoking only by personal perseverance is less than 6% Therefore, drug support is very important for improving the withdrawal rate of smokers At present, the latest drug in this field is still pyrazine Varenicline tartrate, which was launched in the United States in 2006, was approved for smoking cessation Vanillin can selectively bind to α 4 β 2 subtype of nicotinic acetylcholine receptor, which has a high affinity with the receptor subtype This is also the reason why the drug is considered to have a certain role in quitting smoking, because in this subtype, the binding of varenicline produces an agonist activity, and prevents the binding of nicotine to these receptors Sulfonylureas have been proved to be effective and safe for most type 2 diabetes since they came out in the 1950s The main function of these drugs is to stimulate the secretion of insulin by a channel of B cells As the second generation of sulfonylurea antidiabetic drugs with high efficacy and less side effects, the name of glipizide must be familiar Glipizide was developed by Pfizer and approved in the United States in 1984 In 2002, Bristol Myers Squibb Co., Ltd combined glipizide and metformin to form a compound drug metaglip ® which was listed in the United States In clinical trials, compared with metformin alone, metaglip ® containing glipizide significantly (P < 0.001) reduced the mean HbA1c level in patients with type 2 diabetes In 1936, pyrazinamide was synthesized by dalmer and Walter for the first time Later, it was found that pyrazinamide has the activity of anti tuberculosis by accident when studying nicotinamide It is the bioelectronic isochore of nicotinamide Pyrazinamide, as an anti tuberculosis drug alone, has developed drug resistance, but it can play a better role in the combination of drugs At present, Sanofi has put pyrazinamide, isoniazid and rifampin into the market; Novartis has also put their compound drug ethambutol hydrochloride / isoniazid / pyrazinamide / rifampin into the Danish market in 2002 In addition, Lupin tried to replace Novartis' ethambutol hydrochloride with sudoterb, but the study was terminated at the same clinical stage Relevant references: [1] G Vernin The chemistry of heterocyclic flavouring and aroma compounds [2] Wei Shuping, etal Natural-existed Pyrazine Derivants and Their Application to Flavors.Flavour Fragrance Cosmetics 2000(2): 25-31 [3] Zhao Yanlai, introduction to heterocyclic chemistry, higher education press, 1992 [4] Official FDA approval document: https:// / label / 2019 / 212306s000lbl PDF [5] Che Ning, et al Drug therapy for pulmonary hypertension Clinical Medication Journal, 2018,16(2): 5-12 [6] Official FDA approval document: https:// / label / 2019 / 207947s007lbl.pdf [7] Furuta Y, et al Mechanism of action of T-705 against influenza virus Antimicrob Agents Chemother, 2005, 49(3): 981-986 [8] World Health Organization tobacco or health cooperation center, China Center for Disease Control and prevention Office, China Association for tobacco control hospital tobacco control professional committee 2007 Chinese clinical smoking cessation guidelines (trial version) Beijing: People's Health Press 2008 [9] Hughes J R, Shape of the relapse curve and long-term abstinence among untreated smokers Addiction, 2004, 99(1): 29-38 [10] Official FDA approval document: https:// / label / 2019 / 021928s048lbl.pdf [11] Ning Guang et al Efficacy and safety of controlled-release glipizide in the treatment of type 2 diabetes Chinese Journal of Endocrinology and metabolism, 1998, 14 (3): 193-195