Nicotinic acid (CAS 59-67-6) is the only hypolipidemic agent whose activity has been shown both on atherosclerotic lesions and on long term mortality. Unfortunately, its use is hindered by the frequent occurrence ( > 70%) of adverse reactions (i.e. cutaneous rash, pruritus and, most significantly, flush). New prodrugs of nicotinic acid have been prepared by the use of diacylglycerol esters. In the rat, after acute oral administration of these products, a significant decrease of the free fatty acid plasma levels was obtained without the dramatic increase in nicotinic acid plasma levels observed after the oral administration of an equimolecular dose of nicotinic acid. The most interesting ester, S 16961 ((d,l)-1,2-dipalmitoyl-3-nicotinoyl glycerol, CAS 160555-46-4) is undergoing clinical trials.

01 May 1994·Organic Mass Spectrometry

Utility of nicotinoyl derivatives in structural studies of mono‐ and diacylglycerols by gas chromatography/mass spectrometry. Part 1

Author: G. Remberg ; E. Lorbeer ; P. Zöllner

AbstractThe 1‐ and 2‐monoacylglycerols and 1,2‐ and 1,3‐diacylglycerols of saturated and unbranched fatty acids with 8, 10, 12, 14, 16 and 18 carbon atoms were synthesized and subsequently derivatized with nicotinic acid chloride hydrochloride. The resulting nicotinoyl derivatives were examined by mass spectrometry in the case of pure substances and as mixtures by gas chromatography/mass spectrometry (GC/MS). From the electron impact mass spectra, differentiation between mono‐ and diacylglycerols and between the two positional isomers of mono‐acylglycerols and diacylglycerols is possible. The molecular masses of the partial acylglycerols and the identities of the bonded fatty acid were also determined. Similarly to the nicotinoyl derivatives of saturated fatty alcohols, the nicotinoyl derivatives of partial acylglycerols produce a fragmentation pattern that reflects every methylene group of the alkyl chains. These results offer rules for the structure elucidation of partially acylated acylglycerols and probably for mixed diacylglycerols by means of GC/MS, which includes the detection of double bonds and methyl branch positions at the fatty acid alkyl chains. The molecular formulae of all the important fragments in the mass spectra of the nicotinoyl derivatives were confirmed by high‐resolution mass spectrometry. Their structures and fragmentation pathways are proposed.

Arzneimittel-Forschung

Synthesis of 1,2-diacetyl-3-nicotinoyl glycerol derivatives and evaluation of their acute effects on plasma lipids in the rat

Author: Husson, B. ; Volland, J. P. ; Lacoste, J. M. ; Broux, O. ; Mahieu, J. P. ; Duhault, J. ; Cordi, A. ; Espinal, J. ; Boulanger, M.

Nicotinic acid (CAS 59-67-6) is the only hypolipidemic agent whose activity has been shown both on atherosclerotic lesions and on long term mortality.Unfortunately, its use is hindered by the frequent occurrence (>70%) of adverse reactions (i.e. cutaneous rash, pruritus and, most significantly, flush).New prodrugs of nicotinic acid have been prepared by the use of diacylglycerol esters.In the rat, after acute oral administration of these products, a significant decrease of the free fatty acid plasma levels was obtained without the dramatic increase in nicotinic acid plasma levels observed after the oral administration of an equimol. dose of nicotinic acid.The most interesting ester, S 16961 ((d,l)-1,2-dipalmitoyl-3-nicotinoyl glycerol, CAS 153874-14-7) is undergoing clin. trials.Structure activity relation are also discussed.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 1	France	Les Laboratoires Servier SAS	-

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