QSAR of substituted morpholines with antioxidant and squalene synthase inhibitory activity

A quantitative structure-activity relationship (QSAR) study was performed for a series of antihyperlipidemic morpholine derivatives, exhibiting squalene synthase (SQS) inhibitory as well as antioxidant activity (inhibition of lipid peroxidation). Physico/stereo-chemical descriptors of low energy conformations of the compounds were calculated and a number of QSAR models with statistical significance and predictability were produced. The final models include chemical descriptors such as ELUMO, EHOMO-ELUMO gap, cLogP, electrostatic (FNSA1 and RNCS) as well as geometry (YZSHADOW/YZRECTANGLE) descriptors, indicating that electron affinity, along with molecular shape and electrostatic effects play a significant role in the compound's described activities. These models provide some insight on the molecular mechanism of action of these derivatives and assist in the prediction of action in vitro as well as the design of more potent derivatives in the search for effective antiatherosclerosis agents. © Springer Science+Business Media, LLC 2011

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet. In phase 1, the dose-effect relationship of EP2306 on lipids and atherosclerosis was established, and its most effective dose was determined (2 mg/kg). This dose reduced significantly total cholesterol (512 ± 96 mg/dl before versus 320 ± 124 mg/dl after treatment, p < 0.05) and atherosclerotic lesions compared with control animals. In phase 2, the effects of 2 mg/kg EP2306, 2.5 mg/kg simvastatin, and their combination were assessed. Although no significant effect on lipid parameters was observed, there was a significant reduction (35 ± 5%, p < 0.05) of atherosclerotic lesions in animals treated with EP2306, a similar reduction with simvastatin, and a further reduction (48 ± 7%, p < 0.05) when the two agents were combined. In animals treated for 12 weeks with the drugs (phase 3), only EP2306 significantly reduced atherosclerotic lesions by more than 50%, whereas simvastatin alone or in combination with EP2306 had no effect. Treatment with EP2306 did not adversely affect liver transaminases or cause any histopathological changes on various organs of the animals. In conclusion, we have shown that EP2306 inhibits atherosclerosis in vivo, indicating potential as a novel therapeutic agent for coronary artery disease and other atherosclerosis-related disorders. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinhei

Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis

We investigated the effects of EP2306 and EP2302, two novel 2-biphenylmorpholine derivatives, on squalene synthase activity in rabbit and human liver microsomes, lipid biosynthesis, low-density lipoprotein (LDL) receptor expression and LDL protein uptake as well as apoB secretion in HepG2 cells. Both EP2306 and EP2302 inhibited squalene synthase activity dose-dependently. In rabbit liver microsomes, the IC50 values were 33 μM for EP2306 and 0.6 μM for EP2302 whereas in human liver microsomes, they were 63 μM for EP2306 and 1 μM for EP2302. Both EP2300 compounds inhibited cholesterol production by HepG2 cells dose dependently with IC 50 values of 13.3 μM for EP2306 and 3 μM for EP2302. Furthermore, both EP2300 compounds and simvastatin significantly reduced triglyceride synthesis and apoB secretion and increased LDL receptor expression and LDL uptake in HepG2 cells. In summary, we have shown that EP2300 compounds are potent inhibitors of squalene synthase activity in rabbit and human liver microsomes and also they are effective inhibitors of cholesterol and triglyceride biosynthesis in HepG2 cells. These results suggest that EP2306 and EP2302 might prove to be useful for lipid-lowering and treatment of atherosclerosis in vivo. © 2006 Elsevier B.V. All rights reserved