Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes

A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC50 value of 2.43 μM. In polaxamer-407 induced lipoprotein lipase inhibition mo...

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Bibliographic Details
Published in:	European journal of medicinal chemistry Vol. 130; pp. 107 - 123
Main Authors:	Pal, Palash, Gandhi, Hardik P., Kanhed, Ashish M., Patel, Nirali R., Mankadia, Niraj N., Baldha, Satish N., Barmade, Mahesh A., Murumkar, Prashant R., Yadav, Mange Ram
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 21-04-2017
Subjects:	Animals Anticholesteremic Agents - chemistry Anticholesteremic Agents - pharmacology Atherosclerosis Atherosclerosis - prevention & control Azoles - chemistry Azoles - pharmacology Cholesterol - blood Cholesterol lowering agents Cholesterol, LDL - blood Cholesterol, LDL - drug effects Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Hypolipidemic Agents - pharmacology Lipoprotein Lipase - antagonists & inhibitors SOAT inhibitors Sterol O-Acyltransferase - antagonists & inhibitors Triglycerides - blood Urea - chemistry Urea - pharmacology Vicinal diaryl compounds SOAT inhibitors Vicinal diaryl compounds Cholesterol lowering agents Atherosclerosis
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Summary:	A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC50 value of 2.43 μM. In polaxamer-407 induced lipoprotein lipase inhibition model, compound (12d) reduced triglyceride turnover in vivo. Compound (12d) also showed dose-dependent prevention of serum total cholesterol and prevention of LDL-C elevation at a dose of 30 mg/kg. Furthermore, compound (12d) showed potential to stop falling levels of serum HDL-C dose-dependently and improved the atherogenic index. Effect of 12d on body weight, plaque formation and development of atherogenic lesions were studied. Toxicological study of compound (12d) indicated that at a dose of 2000 mg/kg, 12d was devoid of any signs of toxicity or mortality. [Display omitted] •Vicinal diaryl-azole urea analogs as potential SOAT inhibitors were synthesized.•Urea group was shifted from the azole to one of the phenyl rings to study SAR.•Compound 12d emerged as the most potent SOAT inhibitor with an IC50 value of 2.43 μM.•Compound 12d was found to be more potent than Avasimibe (IC50 = 4.01 μM).
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2017.02.038