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Inventory the prodrugs in the heavyweight drugs


Prodrug design/discovery is generally achieved by improving the solubility and/or permeability of compounds, improving their ADME properties, increasing bioavailability, or enhancing targeted delivery. According to the statistics of over 100 heavyweight drugs released in 2016, 9 drug molecules were prodrugs (as shown in the table below), accounting for less than 10%. These prodrugs are mainly hydrolyzed or phosphorylated by enzymes in the human body to form active metabolites. It is predicted that sales of most of the nine drugs will decrease, mainly due to the entry of generic drugs and the launch of more effective drugs.

Sofosbuvir/Sofosbuvir (trade name: Sovaldi) is a nucleotide prodrug. It is metabolized by a variety of enzymes in liver cells (such as CatA/NDPK) to form a pharmacologically active Uracil analog triphosphate (GS-461203, structure as follows). It targets the conservative nucleotide binding bag of NS5B polymerase and terminates the chain polymerization reaction, so as to achieve the purpose of inhibiting the replication of HCV RNA. But last year, the FDA Boxed warning of the risk of hepatitis B (HBV) recurrence. At the same time, competition from Harvoni/Viekira Pak/Zepatier made the golden period of Sofosbuvir sales only three or four years, which is also a significant event in the history of new drug research and development.

Sofosbuvir prodrug active metabolite GS-461203


Fingolimod/Fingolimod (trade name: Gilenya) is a nerve sphingosine-1-phosphate receptor modulator, which is suitable for patients with recurrent Multiple sclerosis to reduce the frequency of clinical deterioration and delay the aggravation of physical disability. After the Lipophilicity prodrug of fengomod enters the central nervous system through oral absorption, it is rapidly phosphorylated through Sphingosine kinase to obtain the bioactive substance (S) - Fengolimod phosphate enantiomer (with the following structure), which can bind with the nerve Sphingosine 1-phosphate receptors 1, 3, 4 and 5 with high affinity, block the ability of lymphocytes to enter and exit from lymph nodes, and reduce the number of lymphocytes in peripheral blood.

Fingolimod prodrug Active metabolite Fingolimod phosphate

Abiolone acetate

Abiraterone acetate/Abiraterone acetate (trade name Zytiga) is a 17 α- Hydroxylase/C17, 20-lyase inhibitor (CYP17), suitable for use in combination with prednisone in patients who have previously received docetaxel containing chemotherapy for castrated refractory prostate cancer (CRP). Apitron acetate prodrug is a Lipophilicity compound (with high permeability). Its octanol water Partition coefficient is 5.12 (Log P) and is particularly insoluble in water. In vivo, it is hydrolyzed into active Abitron (with the following structure) through esterase, which inhibits the expression of CYP17 in testicular, suprarenal gland and prostate tumor tissues and is an enzyme required for androgen biosynthesis. With the entry of more effective CRPC drugs (such as Xtandi) and competition from generic drugs, the market share of Abiolone is expected to gradually decline in the coming years.

Active metabolites of Abiraterone prodrug after hydrolysis

Lai You An Fei Taming

Lisdexamfetamine/Levofloxacin (trade name Vyvanse) was approved for use in children aged 6-12 with ADHD in 2007. The following year, it was approved by the FDA for use in adult attention deficit and hyperactivity disorder (ADHD). It is a once daily prodrug (composed of amphetamine and lysine) central nervous system stimulant approved for use in adult ADHD patients. After oral administration, the product is rapidly absorbed into the blood in the gastrointestinal tract, and then hydrolyzed by esterase to dextran amphetamine (structure as follows) for use. The drug was labeled with a Boxed warning by FDA for stimulating the CNS system, indicating the risk of abuse and dependence. During this period, relevant symptoms should be closely monitored.


Clopidogrel/Clopidogrel (trade name Plavix) is absorbed rapidly after oral administration, and its efficacy can be observed within 2h, which is used to prevent Atherosclerosis and thrombosis events. Thiophenopyridine drugs are basically prodrugs, which need to be metabolized into Active metabolite by the liver Cytochrome P450 enzyme system (CYP450) in vivo before acting. First, the thiophene pyridine parent nucleus is oxidized to form an inactive 2-position oxidation intermediate, and then ring opening forms a Active metabolite, here R-130964 (with the following structure), where CYP2C19 and CYP3A4 play an important role in the formation of Reactive intermediate. R-130964 is a platelet aggregation inhibitor, which selectively inhibits the binding of Adenosine diphosphate (ADP) to its platelet receptor and the activation of secondary ADP mediated glycoprotein GP Ⅱ b/Ⅲ a complex, thus inhibiting platelet aggregation.

Clopidogrel prodrug active metabolite R-130964

Olmesartan ester

Olmesartan medoxomil/Olmesartan ester (trade name Benicar) is hydrolyzed into the active ingredient Olmesartan/Olmesartan (structure as follows) during gastrointestinal absorption. Olmesartan can selectively block the AT1 subtype angiotensin II receptor, thereby blocking the vasoconstriction of angiotensin II, making Vasodilation relax, thus playing a strong antihypertensive role. However, the FDA also has a Boxed warning for the drug, which is prohibited for pregnant women because of its damage or death to the fetus in the abdomen. With the entry of generic drugs, the sales of the drug have gradually declined.

Dabigatran ester

Dabigatran etexilate/dabigatran ester (trade name: Pradaxa) is a direct thrombin inhibitor, which is suitable for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. After Oral administration, Dabigatran ester has strong penetrability. After gastrointestinal absorption, it is hydrolyzed to the main active ingredient Dabigatran/Dabigatran (with the following structure) by esterase, which is also its main metabolic reaction. The bioavailability of Dabigatran is about 6.5%. Dabigatran is not the substrate, inhibitor or inducer of CYP450 enzyme system. It can block both free thrombin and clot binding thrombin.

Dabigatran etexilate prodrug active metabolite Dabigatran

Tenofovir dipivoxil

Tenofovir disoproxil/tenofovir dipivoxil (trade name Viread) is a nucleotide Reverse-transcriptase inhibitor used for HIV and HBV infection. The highly permeable tenofovir diphosphate prodrug is synthesized and transformed into the active ingredient tenofovir diphosphate (with the following structure) in the cell after oral absorption, which can inhibit the viral polymerase by directly competitively combining with the natural Deoxyribose substrate, and play a role by inserting DNA to terminate the DNA chain. The sales of tenofovir dipivoxil will also decline significantly in the next few years, which is due to the better efficacy and convenience of combination drugs (such as Truvada and Atripla, both containing tenofovir), and the hepatitis B B new drug Tenofovir alfenamide (Vemlidy, 25mg) approved by the FDA last year. Compared with the 300mg Viread, it only needs less than one tenth of the dose to obtain similar antiviral effect.

Candesartan cilexetil/Candesartan ester is rapidly hydrolyzed into the active metabolite Candesartan/Candesartan (structure is as follows) in vivo. Candesartan is an angiotensin II AT1 receptor antagonist, which can antagonize the Vasoconstriction effect of angiotensin II by binding with vascular smooth muscle AT1 receptor, thereby reducing peripheral vascular resistance, and is used for primary hypertension. The drug achieved sales of $4 billion in 2011 and has gradually declined to $1 billion in recent years, mainly due to the large-scale entry of generic drugs since 2012.

The prodrug molecules of the above heavyweight drugs all belong to the chemical small molecule category. Of course, antibody coupled drugs (ADC) such as Trastuzumab emtansine also belong to the prodrug category, but there have not been ADC drugs that reach the level of heavyweight drugs yet. There are various design methods for prodrugs, some of which are shown in the figure below. In practice, the choice of prodrug development should be based on the specific PK/PD issues of the project/project (such as - COOH/- SH/- OH/- PO (OH) 2/- NH/- C=O functional groups requiring carriers as shown in the figure below), generally achieving the goal of high solubility and high permeability in BCS classification. At the same time, the metabolism in vivo should also be considered. For example, the active products of the above Sofosbuvir and tenofovir dipivoxil are produced through multi-step metabolism, which is also a problem in the screening of targeted drugs and the discovery of prodrugs. That is, we routinely look for active molecules in the compound library, and the inactive ones excluded may have false negatives, that is, metabolism is not considered.