In-depth analysis of Hengrui's innovative drug design case to explore the golden road of "Yao Mao"

This article is based on several patents of Hengrui Medicine in recent years to understand and learn the design ideas and >

Hengrui Pharmaceuticals, as one of the most innovative large-scale pharmaceutical companies in China

Let’s enjoy several patents filed by Dr.

PART 0 1.

Figure 1 Modification strategy of fluzoparib and AZD6738

As shown in Figure 2, the optimal molecule in Hengrui's patent is 1-A or 1-B.

Figure 2 Modification of AZD-6738 and part of its efficacy data

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

PART 0 2.

Figure 3 AKT1/2/3 inhibitor design ideas

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

Figure 4 AKT1/AKT2/AKT3 enzyme experiment evaluation

PART 0 3.

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.

Figure 5 The published data of patent CN 113135942 A

Figure 6 Data published in patent WO 2021/143821 Al

PART 0 4.

Hengrui has a strong platform advantage: designing molecules basically does not need to consider the difficulty of synthesis.

references:

(1) Li Xin, Chen Yang, He Feng, Tao Weikang, etc.
; Pyrimidooxazine tricyclic derivatives, their preparation methods and

Applications in medicine; the CN 113 004 303 A
.

(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
.

(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
.

(4) Li Xin, Zeng Changgen, He Feng, Tao Weikang; Condensed heteroaryl derivatives, their preparation methods and their applications in medicine; WO 2021/143821 Al
.

(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
.