Innovative drugs: the macrocyclic structure is not only a breakthrough patent, but also a problem-solving

For innovative small-molecule chemical drugs, structure is the basis of all drug characteristics
.
However, the reason why there are so many "me-too" drugs is that it is difficult for similar drugs to escape the range of reported druggable structures that can be inferred by those skilled in the art
.
In order to obtain intellectual property protection, break through the traditional "me-too" vision of the industry, and at the same time have high drug properties, macrocyclic structures are more and more applied to structural design.
Today, through a few examples, Come and share with you the importance of the macrocyclic structure for the structural breakthrough of small molecule chemical drugs
.
1.
Revisiting the classic structure of EGFR.
For chemical innovative drugs, the structure is the basis for the characteristics of all drugs
.
However, the reason why there are so many "me-too" drugs is that it is difficult for similar drugs to escape the range of reported druggable structures that can be inferred by those skilled in the art
.
In order to obtain intellectual property protection, break through the traditional "me-too" vision of the industry, and at the same time have high drug properties, macrocyclic structures are more and more applied to structural design.
Today, through a few examples, Come and share with you the importance of the macrocyclic structure for the structural breakthrough of small molecule chemical drugs
.
Whenever we talk about the big ring and the buckle, we have to talk about the two blockbuster drugs that are the classic target of EGFR in lung cancer, erlotinib and icotinib.
These are also the two structures that industry insiders must talk about.
Review these two drugs first
.
? Erlotinib EGFR inhibitor, developed by Roche's Genentech and Astellas, the first batch was in 2004 (FDA), trade name Tarceva, the drug is mainly used for the treatment of non-small cell lung cancer
.
Tarceva is available as oral tablets, each containing 25 mg, 100 mg or 150 mg of erlotinib
.
Recommended dose for non-small cell lung cancer, 150 mg once daily on an empty stomach
.
?Icotinib development company is Betta Pharmaceuticals (Beta), the first batch was in 2011 (CFDA), the trade name is Conmana/Conmana, it is a locally advanced or metastatic non-small cell with EGFR sensitive gene mutation First-line treatment of lung cancer
.
Conmana is an oral tablet containing 125 mg of icotinib; the recommended dose for adults is 125 mg three times a day
.
So, looking at these two structures from today's perspective, it may not be a big breakthrough for those skilled in the art, but in the past, it was a blockbuster variety that could eventually be developed into a domestic innovative drug.
It can represent the innovative technology level of domestic new drug research and development at that time
.
2.
Possible technical effects of the macroring structure Is the macroring just to break through the patent? From the perspective of structure, it is possible to break through the novelty, but it is difficult to break through the creativity in view of the professionalism of those skilled in the art today
.
Then, some unexpected technical effects must be found, such as some breakthroughs in other druggable characteristics.
Here are a few examples
.
? Activity example In the development process of BACE inhibitor, some researchers have studied and analyzed the protein, and designed a macrocyclic ring structure based on this, and the activity has been significantly improved, as shown in the figure below
.
Figure 2.
1 Macrocyclic structure-improved activity? Selective examples The following macrocyclic aminopyrimidine compounds have good biological activity as multi-target CDK and VEGFR inhibitors.
The introduction of can affect the selectivity of the compound to the target, and the structure is shown in the figure below
.
Figure 2.
2 Macrocyclic structure-selective enhancement? Examples of physicochemical properties Some researchers have reported macrocyclic inhibitors of JAK2 and FLT3, with indications pointing to myelofibrosis and lymphoma; different substituents are modified on the macrocyclic skeleton, water-soluble It has been well improved; of course, this example mainly introduces the modification of the side chain after the cyclization of the macrocycle
.
Figure 2.
3 Macrocyclic structure - physical and chemical properties improvement , everyone can search and study according to their own research direction
.
Here, the author briefly introduces the above-mentioned varieties and other clinical research varieties, and further studies the successful cases of macrocyclic structure
.
? Open-chain crizotinib vs macrocyclic lorlatinib The development companies are both Pfizer, but the time difference is 7 years
.
Crizotinib, which was first marketed in 2011, is an anaplastic lymphoma kinase ALK inhibitor
.
To this end, an upgraded version of lorlatinib was developed and approved for marketing in 2018
.
The structure optimization process is shown in the figure below
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Figure 3.
1 From crizotinib to lorlatinib? The EGFR macrocyclic inhibitor BI-4020 was developed by Boehringer Ingelheim, and the initial lead compound (IC50 in micromolar level) was derived from triple-mutated EGFR (EGFRdeI19/T790M/ C797S) and the wild-type EGFR protein were screened for compounds, and then gradually optimized, the macrocyclic compound BI-4020 was obtained
.
The structure optimization process is shown in the figure below
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Figure 3.
2 The evolution of the results of the EGFR macrocyclic inhibitor BI-4020? The coagulation factor FXIa inhibitor factor XIa is a very hot target in the field of anticoagulation at this stage after factor Xa.
There are many development companies, and there are many The variety has entered the clinic, and the domestic follow is also very tight.
Here, the imidazole structure of BMS company is mainly introduced, and it is gradually developed and promoted with the macrocyclic structure
.
The structure optimization process is shown in the figure below
.
Figure 3.
3 Macrocyclic structure of coagulation factor FXIa inhibitor 4.
Feelings In summary, this is the author's preliminary literacy introduction to macrocyclic structural drugs
.
When we see the process of developing and advancing a variety with a macrocyclic structure, in addition to the breakthrough of patents and the improvement of druggability, there is another very important factor that is often overlooked, and that is the synthesibility of the molecule
.
Macrocyclic structures require not only an in-depth understanding of protein structure and spatial flexibility perception of molecular structure, but also the chemical characteristics and synthesizable characteristics of macrocyclic structures.
Otherwise, it is easy for a medicinal chemistry researcher to gradually move towards The road with high eyes and low hands, divorced from reality without knowing it
.
Therefore, the study of macrocyclic structures is still a path that requires the joint efforts of multiple disciplines to promote the exploration of drug structures
.
References: 1.
Design synthesis and biological evaluation of macrocyclic derivatives as TRK nhibitors.
Sciencedirect 2.
First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib.
Sciencedirect 3.
Macrocyclic skeletons in Application in Research and Development of Antitumor Drugs.
CNKI 4.
Macrocyclic Small Molecule Drugs.
Guo Zongru.
CNKI 5.
Application of Macrocyclic Compounds in Drug Design and Synthesis Strategies.
CNKI