Research progress of deuterium drugs

Deuterium is a stable form of non radioactive isotope of hydrogen in nature Due to its larger atomic mass than hydrogen, C-D bond is more stable (6-9 times) than C-H bond [1,2] The substitution of deuterium for hydrogen in the drug molecules may block the metabolic sites and reduce the generation of toxic metabolites In addition, deuterium can slow down the system clearance rate and thus prolong the half-life of the drug in vivo Therefore, the goal of reducing the toxicity and side effects of the drug can be achieved by reducing the single dose and without affecting the pharmacological activity of the drug [3] Since 2000, deuterium strategy has been widely used in drug research, and it has become one of the most simple and direct ways to break compound patents and avoid the risk of new drug development Figure 1 global deuterium patent application trend in recent 10 years, a group of companies focusing on Deuterium research have achieved great success in the field of new drug research and development Among them, the most famous ones abroad are auspex (Teva acquisition) and concert Auspex was founded in 2001 and listed on NASDAQ in 2014 with only 35 employees In 2015, after the release of phase III clinical trial data of sd-809 (deuterium tetrabenzoquinoxazine), one of its star deuterium products, Teva company invested US $3.2 billion (premium rate of 42%) to put it into the bag In 2017, sd-809, as the world's first deuterium drug, was approved by FDA for the treatment of Huntington's chorea induced abnormal involuntary movement (hd), under the trade name of austedo Yes Compared with undeeuterized tetrabenzoquinoxazine, austedo can significantly slow down the metabolic process, and its half-life is nearly twice that of undeeuterized tetrabenzoquinoxazine [4] Therefore, by reducing the dosage and frequency of medication, the side effects of austedo are less, the depression and suicidal tendency of patients are reduced, and the emergence of withdrawal reaction is inhibited at the same time According to estimate Pharma, austedo's sales volume is expected to reach 667 million US dollars in 2022 Concert was founded in 2006 by Dr Roger D Tung, a Vietnamese American In 2014, it was listed on NASDAQ in the United States The company has only more than 60 employees, with a market value of up to $700 million At present, concert is the company with the largest number of deuterium drug R & D pipelines More than 50 deuterium products have applied for U.S patents, of which nearly 10 deuterium products have entered clinical trials In addition, many large foreign pharmaceutical enterprises such as BMS, GSK and Pfizer also have layout in deuterium field Table 1 clinical situation of deuterium drugs in foreign countries notes: + terminated; + + no development; * continued domestic research progress with a large number of high-tech talents returning to China to devote themselves to the field of pharmaceutical research and development, the domestic new drug development technology has made rapid development, deuterium technology is no exception Among them, Suzhou Zejing and Chengdu Haichuang, two new drug R & D enterprises, are undoubtedly the leaders of domestic deuterium drug development Founded in 2009 by Dr Sheng Zelin, an expert of the national "thousand talents plan", Zejing is committed to the research, development and production of new drugs in the fields of anti-tumor and blood diseases At present, the company has completed round B financing of 400 million RMB, applied for nearly 100 invention patents, and many deuterium products have entered clinical trials Among them, the deuterium drugs donafinil and okatinib developed by the company have obtained the national major special and special approval qualifications respectively At present, phase III and phase I clinical trials are in progress Founded in 2013 by Dr Chen Yuanwei, an expert of the national "thousand talents plan" and a professor of Sichuan University, Chengdu Haichuang has successively obtained 30 million strategic investment from Chengdu Yingchuang power and 30 million strategic investment from hisic Using its core deuterium drug technology (DDT), the company has developed a number of innovative drugs, including the treatment of prostate cancer, breast cancer, gout and other diseases Its first deuterium product hc-1119, which has entered the clinical trial, has been transferred to Sichuan hisic with more than 30 million yuan Hc-1119 is a deuterium substitute product of azarulamine, which is used for the treatment of castration resistant prostate cancer At present, phase I / II clinical trials are being conducted in West China Hospital Recently, a global phase III clinical trial expert consultation meeting of hc-1119 was held in the United States, and phase III clinical trials will be started soon According to Haichuang and hisic, hc-1119 is expected to be listed in China in 2020, and the market space in the future is expected to exceed 2 billion yuan Table 2 research progress of deuterium in China According to the conclusion of clinical examination and approval of deuterium substitute products in China at present, many deuterium substitute drugs with clinical advantages have obtained the qualification of national major special or special examination and approval channels, such as danafinil, jaketinil and okatini, hc-1119 of Chengdu Haichuang / HISCO, dc-001 of Chongqing University of Arts and Sciences In China, there is a positive attitude towards the innovation caused by the significant isotope effect between deuterium and non deuterium drugs In addition, according to the case of austedo approved by FDA, one of the challenges faced by researchers and evaluation departments mainly focuses on how to bridge the comparability and safety of the results of existing non clinical and clinical trials [5] References: [1] Lin C, Chen g, Chen g, et al A calculated analysis of dasatinib interrupts cell cycle progress and displays anti non small cell lung cancer activity in vitro and in vivo [J] International Journal of cancer, 2012, 131 (10): 2411-2419 [2] Robert F, Gautier D, dubrile B the solar system D / H ratio: observations and themes [J] Space science reviews, 2000, 92 (1-2): 201-224 [3] Gant t g using deuterium in drug discovery: leaving the label in the drug [J] Journal of medical chemistry, 2014, 57 (9): 3595-3611 [4] Liu Jie Progress of deuterium [J] Chemical design communication, 2016, 42 (4): 199-199 [5] Gao Guanghua, Wang Haixue Research and development case analysis of deuterium drug austedo (deuttrabenazine) [J] China Journal of new drugs, 2017 (18): 2159-2165 Statement: this point of view only represents the author and does not represent the position of yaozhi.com, welcome to exchange and supplement in the message area; 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