Important Compound Classes
Title
Preparation of Benzimidazolone Derivatives as Novel Diacylglyceride O-Acyltransferase 2 Inhibitors
Patent Publication Number
WO 2022/076495 A1
URL
Publication Date
April 14, 2022
Priority Application
US 63/089,068
Priority Date
October 8, 2020
Inventors
Lim, Y.-H.; Ashley, E. R.; Bao, J.; Cheng, C.; Roane, J. P.; Southgate, E. H.
Assignee Company
Merck Sharp & Dohme Corp., USA
Disease Area
Hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney diseases, and heart failure
Biological Target
Diacylglyceride O-acyltransferase 2
Summary
Triacylglycerols (TGs) serve several functions in living organisms. One function of TGs is in the storage of energy. TGs also play a role in the synthesis of membrane lipids. TG synthesis in cells may protect them from the potentially toxic effects of excess fatty acid (FA). The glycerol phosphate and the monoacylglycerol pathways are the major pathways for the biosynthesis of TG. However, the last step in the synthesis of TG involves the reaction of a fatty acyl-CoA and diacylglycerol (DAG) to form TG. The reaction is catalyzed by acyl-CoA:diacylglyceride acyltransferase (DGAT) enzymes. Two DGAT enzymes have been identified: DGAT1 and DGAT2. Inactivation of DGAT2 impairs cytosolic lipid droplet growth, whereas inactivation of DGAT1 exerts the opposite effect.
DGAT2 appears to be the dominant DGAT enzyme controlling TG homeostasis in vivo. The metabolic role of DGAT2 has been mostly understood from efforts exploiting antisense oligonucleotides (ASO) in rodents. In this setting, DGAT2 knockdown in ob/ob mice with a DGAT2 gene-specific ASO resulted in a dose-dependent decrease in very low density lipoprotein (VLDL) and reductions in plasma TG, total cholesterol, and ApoB. Another study showed that diet-induced hepatic steatosis and insulin resistance were improved by knocking down DGAT2 in rats.
The present application describes a series of novel benzimidazolone derivatives as DGAT2 inhibitors for the treatment of hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney diseases, and heart failure. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
X, Y, and Z = N or C(R5);
R1 = phenyl unsubstituted or substituted with 1, 2, or 3 R6, 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R6, 8- or 10-membered fused heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R6;
R2 = phenyl unsubstituted or substituted with 1, 2, or 3 R7, 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R7, C1–6alkyl unsubstituted or optionally monosubstituted or disubstituted with halogen, OH, CF3, or CN;
R3 = 4- or 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, −(C1–6)alkyl-aryl; and
R4 = H or −(C1–3)alkyl.
Key Structures
Biological Assay
The DGAT2 enzymatic activity assay was performed. The compounds described in this application were tested for their ability to inhibit DGAT2. The DGAT2 IC50 (nM) are shown in the table below.
Biological Data
The table below shows representative compounds tested for DGAT2 inhibition and lists the biological data obtained from testing the representative examples.
Claims
Total claims: 44
Compound claims: 40
Composition claims: 2
Method of treatment claims: 1
Use of compound claims: 1
The author declares no competing financial interest.
References
- Darabi M.; Kontush A. High-density lipoproteins (HDL): Novel function and therapeutic applications. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2022, 1867, 159058. 10.1016/j.bbalip.2021.159058. [DOI] [PubMed] [Google Scholar]
- Snaebjornsson M. T.; Janaki-Raman S.; Schulze A. Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer. Cell Metab. 2020, 31, 62. 10.1016/j.cmet.2019.11.010. [DOI] [PubMed] [Google Scholar]