In 2022,Li, Xing-Zi; Jiang, Shi-You; Li, Guo-Qiang; Jiang, Qian-Ru; Li, Jue-Wan; Li, Chen-Chen; Han, Yu-Qin; Song, Bao-Liang; Ma, Xin-Ran; Qi, Wei; Qiu, Wen-Wei published an article in European Journal of Medicinal Chemistry. The title of the article was 《Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol》.Related Products of 87120-72-7 The author mentioned the following in the article:
HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 (I) as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (II) (QH536) showed an EC50 of 0.22μM in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC50 = 0.43μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH. The results came from multiple reactions, including the reaction of tert-Butyl 4-aminopiperidine-1-carboxylate(cas: 87120-72-7Related Products of 87120-72-7)
tert-Butyl 4-aminopiperidine-1-carboxylate(cas: 87120-72-7) belongs to anime. Primary amines having a tertiary alkyl group (R3CNH2) are difficult to prepare with most methods but are made industrially by the Ritter reaction. In this method a tertiary alcohol reacts with hydrogen cyanide (HCN) in the presence of a concentrated strong acid; a formamide, RNH―CHO, is formed first, which then undergoes hydrolysis.Related Products of 87120-72-7
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem