? Patent analysis of small molecule drug design (WuXi AppTec ddsu article)

WuXi AppTec ddsu (Domestic Discovery Service Unit) is believed to be familiar to researchers who are engaged in molecular design of innovative drugs
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This article tries to discuss some ideas for drug design from several small molecule innovative drug patents filed by ddsu in recent years
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#01 Let’s start with KRAS, one of the hottest targets
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("Snooping" on the KRAS G12C patents of major famous companies: you must beware of crashes.
) In 2018, LiuYi et al.
in Cell (Matthew R.
Janes, Yi Liu et al.
, Cell, 2018, 172,578-589) .
) The covalent binding inhibitor ARS-1620 that targets the KRAS G12C mutation is publicly reported.
This compound has good metabolic stability, exhibits nM-level cellular anti-proliferative activity at the cellular level, and is effective in pancreatic cancer MIA.
-Paca2 cells can effectively inhibit tumor growth in subcutaneous xenograft tumor models
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WO2018/064510A1 discloses compound Exp3, but does not provide characterization data and test results
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WuXi R&D personnel published the structure of compound 49 in patent WO2019141250.
The final result showed that in the rat pharmacokinetic evaluation experiment, one of the axial chiral isomers of compound 49 showed a higher level than ARS-1620.
Exposure (7739 vs 2316 nM*h) and better oral availability (52% vs 22%); compound 49 is superior to ARS-1620 in the human non-small cell lung cancer NCI-H358 subcutaneous allograft tumor model In vivo drug effect, and the anti-tumor effect has a dose-dependent trend
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From ARS-1620 to compound 49, the design idea of ​​skeleton transition was adopted.
The quinazoline nucleus in 1620 was replaced with the skeleton of pyrimidopyridone, and by changing the substituent group on the skeleton (chlorine was changed to CF3), The aromatic ring substitution group in the left side chain (fluorine and hydroxyl are replaced by diaminodichloro) balances the physical and chemical properties of the new molecule, and finally a candidate molecule with better druggability is obtained
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Subsequently, the structure of compound 1-11A was disclosed in WO2020259573.
The N in the aromatic ring on the right was changed to C, and a 7-membered oxygen heterocycle was formed with piperazine
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There is no direct comparison between 1-11A in this patent and the compound 49 in the previous patent.
The conclusion is that: Compound 1-11A shows a good in vivo drug in the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model.
Effective
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At a dose of 3 mg/kg, 1-11A has a strong inhibitory effect on tumor growth, while increasing the dose to 10 mg/kg, 1-11A has a stronger tumor inhibitory effect than that at 3 mg/kg, and the tumor growth inhibition rate reaches 83.
9%
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In the patent published in 2021, WuXi R&D personnel also changed a large circle based on AMG510.
Under the same dosage, the total system exposure, peak concentration and bioavailability of the 003 compound after oral administration are better than those of the reference compound.
AMG510, showing excellent pharmacokinetic properties
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The design idea of ​​the big ring is often used to solve the problem of drug resistance and can also affect the physical and chemical properties.
However, in most cases, it will increase the difficulty of synthesis and increase the cost of CMC
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Pfizer developed the third-generation ALK tyrosine kinase inhibitor-loratinib, which is effective against crizotinib and second-generation ALK inhibitor-resistant lung cancer, and due to its high blood-brain barrier permeability, Non-small cell lung cancer with central nervous system metastasis can also play a better role
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#02 Patent WO 2020/239107 announced a class of tetracyclic compounds as Cdc7 inhibitors.
This patent was jointly applied by Zhengda Tianqing and Nanjing Mingde
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TAK-931 is a Cdc7 inhibitor.
It is currently in clinical phase II.
The development of a new generation of metabolically stable Cdc7 inhibitors is in clinical demand
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According to the data published in the patent, compound 1-1 hydrochloride has an IC50 of Cdc7/DBF4 enzymatic inhibitory activity = 3.
02 nM, and an inhibitory activity of COLO205 cell proliferation IC50 = 13.
8 nM; when mice are orally administered 10 mg/kg by gavage The bioavailability is 71.
4%; the clearance rate is 35.
2mL/min/kg; none of these data has found a positive reference result
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According to the data of the compound in the SW620 human colon cancer xenograft tumor model in Figure 2, the hydrochloride of compound 1-1 was administered twice a day at a dose of 7.
5 mg/kg, and the tumor volume was compared with TAK-931, 40 mg.
/kg, the BID ratio is reduced by 3 to 4 times; not only the dose is reduced, but the efficacy is also better
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From the point of view of molecular structure design, the methyl group of pyrazole in compound TAK-931 forms a seven-membered ring with the extended substituents on thiophene.
Through this conformational constraint method, the relationship between the candidate compound and the target protein is changed.
In combination, from this example, a better effect has been achieved
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#03 Patent WO 2019/154261 discloses a class of pyridine derivatives related to the KMD5 pathway; epigenetic combination with the regulation of DNA damage repair is an effective way to treat some malignant tumors, and at the same time, it has good synergistic prospects
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Members of the KMD5 family are abnormal in breast cancer and have great market potential
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WO2016168349 reports that compound GS-5801 is a kind of KMD5 inhibitor with pyridine carboxylate structure
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Figure 3 GS-5801's transformation ideas and part of the pharmacodynamic data.
According to the data published in the patent, the IC50 of KDM5 = 6 nM was detected by the TR-FRET format experiment.
In the results of the pharmacokinetics in Male CD-I mice, because There is no data comparison of positive drugs in the patent; the clearance rate, AUC and F are all good
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At the same time, compound 1 was tested for inhibition of five CYP isoenzymes and hERG potassium ion channels, and there was no hidden danger of safety
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From the point of view of molecular structure design, the exposed NH in compound GS-5801 is connected with aliphatic substitution and closed with the ethyl ring on the amide N to form a seven-membered ring.
Through this conformational constraint method, it changes The combination of the candidate compound and the target protein seems to have achieved better results from this example
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The author believes that the design ideas of the above GS-5801 and TAK-931 are similar to those of Betta Pharmaceuticals' Icotinib and Hengrui's Famitinib
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The above shared several cases of drug molecular design and modification.
The above part is just my personal opinion, and may not be consistent with the actual research and development ideas
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Interested readers can pay attention to which domestic pharmaceutical companies have been transferred to the above several patents
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References: (1) Yang Yaxun, Jiang Zhigan, He Haiying, etc.
; WO 2019/154261, a periphagic derivative related to the KMD5 pathway
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(2) Li Gang, Lu Lun, Zhang Zhibo, etc.
; Tetracyclic compounds WO 2020/239107 as Cdc7 inhibitors
.
(3) Ding Zhaozhong; as a seven-membered heterocyclic derivative of KRAS G12c mutein inhibitor WO 2020/259573
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(4) Li Qiu, Wang Jianfei, Hu Guoping; Macrocyclic compounds as KRAS inhibitors WO 2021/147965
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(5) Li Qiu, Wang Jianfei, Hu Guoping; Macrocyclic compounds as KRAS inhibitors WO 2021/147967
.