In-depth analysis of Hengrui's innovative drug design cases, exploring the gold-digging road of "Yao Mao"

In the previous article, through patent analysis, we learned some ideas of WuXi ddsu small molecule innovative drug design (Patent Analysis of Small Molecule Drug Design (WuXi AppTec ddsu article)).
This article is based on Hengrui Pharmaceuticals Several patents in recent years to understand and learn the design ideas and >
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Focus on how each of Hengrui's candidate molecules evolved step by step
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Hengrui Pharmaceuticals, as one of the most innovative large-scale pharmaceutical companies in China
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Since Hytrobopar was approved for listing, the number of marketed innovative drugs has increased to 8 (the largest number of domestic pharmaceutical companies)
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By searching for part of Hengrui Medicine's patents, the author feels that Hengrui's small molecule innovative drug design features are: practical, simple, and efficient; how cool and imaginative the design is, it is useless to not be a medicine
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In the domestic atmosphere of degrading me-too and me-better, and advocating first-in-class, the value and difficulty of making me-too have also been seriously underestimated.
At present, it seems that only the transformation of natural products can be used as FIC in China.
Hope
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As Dr.
Li Xin, the inventor of fluzoparil, said, "A good compound needs to repeatedly optimize the structure, refine the group, and continuously improve its activity, selectivity, pharmacokinetic absorption, etc.
, and its toxic and side effects need to be minimized.
"
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The final listing of a drug has gone through numerous obstacles, and we should be in awe
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Let’s enjoy several patents filed by Dr.
Li Xin.
Everyone knows the story of fluzoparil.
The difficulty of the project was solved by the strategy of amide electrons and other triazoles and ring closure; amides were arranged into triazoles.
The strategy is very common, but the isosteric triazole ring is very clever, and the different positions of N in the triazole can also have an important effect on the binding of the drug molecule and the target protein.

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PART 0 1.
In the patent published in 2021 (CN 113004303), a class of pyrimidooxazine tricyclic derivatives as ATR kinase inhibitors is mentioned; Hengrui follows AZD-6738, which was previously published in 2018 In JMC, AstraZeneca shared the idea of ​​changing from the tool compound AZ20 to the clinical compound AZD-6738.
On the basis of ensuring the cell viability as much as possible, the indole in AZ20 was changed to azaindole and methyl sulfone.
One of the sulfur-oxygen double bond is changed to a sulfur-nitrogen double bond; through the strategy of skeleton transition and isosteric, Clogp is reduced, tPSA is increased, and finally the water solubility of the compound is greatly improved, and it has no inhibitory effect on CYP3A4
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Changing the benzene ring to pyridine can increase polarity and improve water solubility, but clinical compounds containing sulfur and nitrogen double bonds are rare
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Next, let's look at Hengrui's transformation strategy
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As shown in Figure 2, the optimal molecule in Hengrui's patent is 1-A or 1-B.
The difference from AZD-6738 is that an oxygen-containing 6-membered ring is closed on the morpholine ring and the pyrimidine ring.
I don’t know the follow-up Whether it is an amide ring or a nitrogen-containing 6, 7-membered ring
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Through the conformational constrained modification strategy, the optimal molecule can inhibit ATR enzyme with an IC50 of 4 or 5 nM; the more advantageous one is its weak inhibitory activity on ATM enzyme, DNA?PK enzyme, PI3K enzyme and mTOR enzyme.
Compound 1- A or 1-B has good selectivity to ATR enzyme
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In the solubility test, it showed suitable solubility; but in the test of the pharmacokinetic parameters of nude mice, CL/F = 217 ml/min/kg; the clearance rate was obviously too fast
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Because there is no reference to AZD-6738 in the patent, it is not easy to compare directly
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PART 02.
In patent WO 2021/121276, a class of fused tetracyclic derivatives are published as AKT 1/2/3 (AKTpan) inhibitors; PI3K signaling pathway participates in and regulates multiple oncogenes and anti-cancer Gene expression and excessive activation of the PI3K/AKT signaling pathway have been confirmed to be related to the occurrence of a variety of cancers.
There is a clinical need to develop new AKT1/2/3 (AKT pan) inhibitors
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AKT1/2/3 (AKT pan) inhibitors AZD5363 (AZ) and GDC0068 (Roche) have achieved breakthrough results in phase 2 clinical trials, and their combined use with other anticancer drugs can treat triple-negative breast cancer, ER+ breast cancer and prostate cancer The treatment produced obvious effects
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At present, the two AKT1/2/3 (AKT1pan) inhibitors AZD5363 and GDC0068 have successfully advanced to the phase 3 clinical phase
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Observe the structural characteristics of GDC0068 and AZD5363, connect the red part of GDC0068 and the blue part of AZD5363 through the strategy of molecular hybridization, and then the piperazine ring and the pyrrole ring form a seven-membered oxygen ring
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In this patent, there is only an enzymatic experiment evaluation, and the results show that the isomers with a longer retention time have a good inhibitory effect on the AKT1/AKT2/AKT3 enzyme
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PART 03.
In the above two examples, morpholine or piperazine is used to associate an oxygen-containing 6- or 7-membered ring with the pyrimidine or pyrrole in the ortho position below.
This idea seems to be the same as the previous hot KRAS inhibitor transformation (" Spy on the KRAS G12C patents of famous companies: the same is true, you need to beware of crashes), AZ’s strategy is very similar, all through the piperazine or morpholine ring and the ortho ring to form a large oxygen ring
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In another ATR inhibitor patent of Hengrui (CN 113135942 A), the best possible compound 3 is obtained from AZD-6738 backbone transition, isosteric, and ring closure.
The IC50 of compound 3 for ATR enzyme inhibition It is 9 nM, and the selectivity is no problem, but the PK data of nude mice has not been disclosed.
I don’t know if the problem of too fast clearance has been solved, and what are the results of solubility and inhibition of CYP3A4; the latest ATR inhibitor applied in 2021 In the patent (WO 2021/143821 Al), the ring is closed in one direction, and the best possible compound 1-A or 1-B or compound 2 or compound 3 is obtained.
These compounds have their own advantages: the activity of compound 3 Preferably, the clearance of compound 2 is the slowest, compound 1-A or 1-B has better selectivity, and compound 2 may continue to be modified
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PART 0 4.
The above discussed several patents applied by Hengrui Pharmaceuticals in recent years.
I couldn't help but feel the hardship of making medicine.
The designer is like a blind man touching the elephant.
Seeing the successful result, it is simple to talk on paper
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In specific operations, the problems and difficulties faced are countless
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Hengrui has a strong platform advantage: designing molecules basically does not need to consider the difficulty of synthesis.
There are a lot of doctoral students from the Chinese Academy of Sciences and 985 colleges and universities who are opening up the synthesis route.
The recruitment conditions for project managers are also 985 college doctors, and many others are not one by one.
Enumerated, this kind of luxury is the envy of many companies
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Of course, Hengrui has a lot of projects, rich pipelines, and opportunities for grassroots employees to exercise.
WuXi’s vision is to "let the world have no difficult medicines and no incurable diseases.
" Although Hengrui is not so loud.
The slogan, but the diligence, hard work, persistence, and optimism of Hengrui's primary medical staff have deeply infected the author.
Maybe the project you participate in and manage today will enter the clinic tomorrow and be listed the day after tomorrow
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Looking forward to Hengrui's return to the top
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References: (1) Li Xin, Chen Yang, He Feng, Tao Weikang, etc.
; Pyrimidooxazine tricyclic derivatives, their preparation methods and their applications in medicine; CN 113004303 A
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(2) Li Xin, Dong Ping, Fu Jiqiang, He Feng, etc.
; Condensed tetracyclic derivatives, their preparation methods and their applications in medicine; WO 2021/121276 Al
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(3) Li Xin, Yang Fang, Pingbin Jiang, HE peak Taowei Kang; fused pyrimidine derivatives, their preparation and their use in medicine; the CN 113 135 942 A
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(4) Li Xin, Zeng Changgen, He Feng, Tao Weikang; Condensed heteroaryl derivatives, their preparation methods and their applications in medicine; WO 2021/143821 Al
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(5) Philip J.
Jewsbury; Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent; J.
Med.
Chem.
2018, 61, 9889?9907
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