Heavy Drug Discovery II - Engele Net

Diabetes is an ancient disease, as documented in the Emperor's Book, traditional Chinese medicine is called "thirsty disease", also known as "rich disease".
there are currently about 463 million diabetes patients in the world, and at an alarming rate of increase, China has about 116.4 million diabetes patients, the number of cases in the world's first.
This is a chronic, comprehensive disease caused by an absolute or relative deficiency of insulin, or a decrease in the sensitivity of the target cells to insulin, mainly a sugar metabolic disorder, in which type 2 diabetes occurs as a result of a joint effect of insulin resistance and β cellular dysfunction.
in the last decade, there are two main types of small molecule oral antisaccharides studied, namely DPP-IV inhibitors (Gretin drugs) and SGLT2 inhibitors (Grete drugs).
this paper, the author will make a simple introduction to the discovery and optimization process of Engele Net.
, originally developed by Grigg Ingham, later and Lilly, was first approved for listing by the European Medicines Agency (EMA) on 22 May 2014 and by the US F F The DA was approved for listing on December 26, 2014 by the Japan Medicines and Medical Devices Administration (PMDA), and on September 21, 2017 by the CFDA for listing in China under the ®.
sales, Engel's net global sales reached $3,354 million, according to its 2019 annual report, and it is a compound with Engele Net.
2015 Grigg Ingelheim approved the listing of "Ingley Net/ Hydrochloric Acid Metformin", "Ingle Net/Ligligletin", also has a good market performance;
Its structural and 3D models are as follows: Engele net development process, comparative advantage, because it has six similar drugs on the market before, of course, but also faced with a narrow development space, breaking through the patent difficult adverse factors.
Grigg Ingham first used the structure of the Figure 1 pass as the pilot structure, and carried out a large number of official group derivatives of R1-R7.
figure 1 pilot structure R1, R2 is mainly H, F, Br, I, 1-4 carbon alkyl, 2-4 carbon ene, 3-7 carbon cyclane, cyanide, methoxygen, replace methyl, etc.; 3 carbon alkyl, 1-3 carbon alkyl, halogen-replaced 1-3 carbon alkyl, etc.; R6, R7a, R7b, R7c mainly H, 1-8 carbon alkyl, 1-8 carbon alkyl, alkyl 1-3 carbon alkyl, etc.
by synthesizing a large number of molecular and molecular activity tests, it was finally found that the Figure 2 pass-through has good activity, and continues to have a large number of derivatives of R8.
2 after the initial optimization of the general part of the optimization molecules shown in Figure 3, and synthesis of a relatively small number of molecules for activity testing, and finally found compound 5, that is, the discovery of Engele net.
3 part optimizes the molecule and then the researchers study the compound's synthesis path.
synthesis route 1 (Figure 4), starting with 5-bromine-2-chlorobenzene acid as the starting material, through the steps of acrylamide, fuchsylization, reduction, de-protection, upper protection and other steps to synthesize Engele net.
Figure 4 Synthesis Route 1 Synthesis Route II (Figure 5), starting with 2-chlorine-5 iodized benzoic acid as the starting material, after acrylamide, fuchsylization, replacement, reduction and other steps to synthesize Ingle net.
Figure 5 Synthesis route two of course, route one used butyl lithium reagents and low temperature conditions, harsh conditions, route two with mild format reagents instead of butyl lithium, the temperature does not need to be controlled to -78 degrees so low, to get ll.1 directly after the use of triethyl chlorosilane reduction recrystaining can obtain high purity of Engele net, the method can already be 100 kg level of production.
, of course, better routes are always on the way.
References: 1. SGLT2 inhibitor diabetes drug synthesis route summary, drug crossing; Chinese Journal of New Drugs, 2016, Volume 25, Issue 6; US7579449B2；4. WO2006120208A1；5. WO2011039107A1。