Development of Novel Benzomorpholine Class of Diacylglycerol Acyltransferase I Inhibitors

Abstract

Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (23n). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound 23n conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge.

Deconstructing the DGAT1 Enzyme: Membrane Interactions at Substrate Binding Sites

“…The information provided by this study on synthetic peptide corresponding to substrate binding sites should therefore contribute to understanding of the functioning of theses enzymes in metabolic disorders [33], and the development of novel inhibitors [34]. …”

“…Given the DGAT1 enzymes represent interesting therapeutic targets in obesity [ 5 – 7 ], insulin resistance [ 10 , 31 ], and in hepatitis C virus infection [ 32 ], it is important that DGAT1 structure-activity relationships are characterized, especially in the absence of any crystal structure of this enzyme or a close homologue. The information provided by this study on synthetic peptide corresponding to substrate binding sites should therefore contribute to understanding of the functioning of theses enzymes in metabolic disorders [ 33 ], and the development of novel inhibitors [ 34 ].…”

Study on the 4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone using FT-IR, 1H and 13C NMR, UV-vis spectroscopy, and DFT/HSEH1PBE method

“…Very recently, we studied some 3(2H)-pyridazinone compounds [2][3][4][5]. In this content, as a continuation of our spectroscopic and quantum chemical calculation studies on the mentioned pyridazinones, we found that the 4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone isalso to be worth to investigate by using the FT-IR and UV-vis spectroscopies and quantum chemical calculations [6][7][8][9][10][11][12]. However, the spectral and theoretical studies on this compound used as an analgesic and anti-inflammotory drug in the pharmacologywere not taken place in the literatureto our best knowledge.…”

“…However, the spectral and theoretical studies on this compound used as an analgesic and anti-inflammotory drug in the pharmacologywere not taken place in the literatureto our best knowledge. The 4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone compound has two scaffold six-membered rings called pyridazinone and morpholinewhich is considered an important building block in the medicine chemistry field [11,12]. However, the pyridazinone ring has two adjacent nitrogen atoms at 1 and 2 positions in a six-membred ring and a carbonyl group at 3 position while the morpholine block possess one nitrogen and an oxygen atoms in the ring [13,14].…”

Efficient and Selective Palladium‐Catalysed C‐3 Urea Couplings to 3,5‐Dichloro‐2(1H)‐pyrazinones

“…We have evaluated the 2(1 H )‐pyrazinone as a P 3 core structure in the development of new inhibitors of the HCV NS3 protease and drug‐resistant variants,8 and we eventually discovered that a tert ‐butylurea functionality in the 3‐position of the 2(1 H )‐pyrazinone resulted in an increased inhibition of the HCV NS3 protease (e.g., I , Figure 1). 7c…”