Pfizer has applied to the United States for emergency use of Paxlovid's antiviral drug this month, which has been shown to be very effective in preventing hospitalization and death of high-risk patients. Among high-risk patients with new infections who receive treatment within three days of onset of symptoms, Pfizer’s drugs have been shown to reduce hospitalizations or deaths by 89%. On the 19th of this month, the U.S. government announced that it would spend US$5.3 billion (33.8 billion yuan) to purchase 10 million Pfizer’s new crown drugs. Pfizer will start to provide these new crown tablets to the US government later this year and continue until 2022. The end of the year (of course, whether it can be implemented depends on the approval of the US Food and Drug Administration FDA).
The core ingredient of Paxlovid is PF-073213322. The research and development of PF-073213322 began during SARS. At that time, Pfizer had developed PF-00835231, but with the end of SARS, the development was terminated. When the new coronavirus broke out in 2020, researchers found that the gene sequence of the new coronavirus was exactly the same as the key site of the SARS virus's main protease, making it possible to use the SARS drug PF-00835231 in the research of the new coronavirus, so Pfizer used PF-00835231 As a basis, restart the research and development of drugs.
PF-00835231 (Compound 1) inhibits the activity of the main protease of the virus. Its anti-toxicity is very strong, but its water solubility and tissue absorption are not good. It can only be administered orally, only by intravenous injection. In order to improve the permeability and oral availability of 1, the researchers changed the α-hydroxymethyl ketone of 1 to cyano to obtain compound 2. The results show that this cyano compound improves the water-soluble absorbability of the drug, while also significantly reducing its antiviral power. Subsequently, the researchers introduced azabicyclo and benzothiazole to obtain compound 3. The permeability of compound 3 is significantly improved, but the activity is far inferior to 1. The researchers changed the indole to methyl sulfonamide to obtain compound 4. After further optimization, compound 5 containing trifluoroacetamide was obtained. Change the benzothiazole of 5 to cyano to obtain PF-07321332 (namely compound 6). Finally, considering the compound's bioavailability, antiviral activity, and industrial production feasibility, the compound 6 was used as an active drug to carry out clinical trials.
When studying drug metabolism, researchers discovered that cytochrome P4503A4 enzyme oxidizes multiple sites of PF-07321332 to inactivate it. Adding cytochrome P4503A4 enzyme inhibitor, the inactivation rate of PF-07321332 in the human body will be significantly reduced. Therefore, the researchers used co-administration with the potent cytochrome P450 3A4 enzyme inhibitor ritonavir (RTV) to increase the antiviral activity of PF-07321332 in the clinic. The results showed that co-administration can significantly increase the blood concentration of oral drugs, thereby improving Effectively fight viruses and improve clinical effectiveness.
SARS virus and new coronavirus belong to the same type of B coronavirus, but their genetic homology is not very high. But fortunately, their proteases are highly consistent. Compared with the relatively variable spike protein, highly consistent viral proteases are the most critical and effective targets of the virus.
At the same time, according to Reuters, Pfizer stated that it has signed an agreement with the "Medical Patent Pool (MPP)" supported by the United Nations to authorize pharmaceutical factories to produce generic drugs for the novel coronavirus developed by it. According to the agreement, as long as Paxlovid is authorized for use by regulatory agencies in various countries, qualified generic drug manufacturers authorized by MPP will be able to provide the drug to 95 countries, which is expected to cover about 53% of the world's population.
Whether Paxlovid, with its product advantages and clinical access advantages, can become the terminator of Covid-19 that has spread to the world, and truly become the hope of the people, let us wait and see!
Source: Official Account Pharmaceutical Affairs
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