New Antihypertensive Agents
Search and Investigations of Antihypertensive Action Among 1-Alkyl-2-acyl-glycerides
Tech Area / Field
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
State Research Institute of Organic Chemistry and Technology, Russia, Moscow
- Moscow State University / International Biotechnology Center, Russia, Moscow
- University of Glasgow, UK, Glasgow\nWright State University, USA, OH, Dayton\nTechnology Development Company / Moscow Representative Office, Russia, Moscow\nMedical College of Wisconsin, USA, WI, Milwaukee
Project summaryDespite considerable efforts in the development of antihypertensive therapeutics, hypertension still affects about 20% of adult population and is the major factor of cardiovascular morbidity and mortality. In this connection the design of new classes of antihypertensive drugs is one of the main goals of the modern cardiovascular medicine.
The objective of the Project is to develop methods for preparation and to study mechanisms of action for a new class of lipids - precursors, metabolites and structural analogues of the platelet activating factor (PAF) with antihypertensive effect.
Direct effect of PAF on vessel walls leading to vasorelaxation and massive release of vasoconstrictors, caused by PAF-induced excitation of platelets, granulocytes and macrophages contribute to this phenomenon.
However, the pharmacological usage of PAF as an antihypertensive compound is complicated due to its high toxicity and short-lasting hypotensive effect as was shown by in vivo investigation.
Efforts to modify PAF structure resulted in lower toxicity and adequately lower hypotensive effect. More considerable change of the structure - elimination of a phosphocholine residue from PAF molecule - led to 1-alkyl-2-acetyl glycerol with hypotensive effect and without any toxic effect. However, this compound is chemically unstable because of lability of acetyl group (during storage).
We suggested that replacement of the labile acetyl group in PAF derivatives, 1-alkyl-2-acetyl glycerols, by stable isosteric group will lead to a new class of stable compounds possessing low toxicity and prolonged antihypertensive effect. Our preliminary results confirm this hypothesis: we did not observed toxic effect for rats in concentration 100 mg/kg.
The single injection of the synthesized compounds at the dose of 1 mg/kg reduced arterial tension in hypertensive rats by 30 %, and long-lasting hypotensive effect was observed.
Thus, a group of lipid bioregulators with the following structure is supposed to be obtained:
where R is lipid residue (CH2)n; n = 14 - 22 (preferably 16, 18);
R’ - hydrocarbon fragment (CH2)nCH3 (n = 2 - 10), alkyl- or dialkylamines, whose alkyl groups may include aryl fragments or heteroatoms (N, O, S).
As a result of directed synthesis of lipids of selected structure, substances will be found substantially reducing arterial tension in test animals; mechanism of action of these compounds will be studied at cellular (blood cells system, animal and human liver cells) and organism levels; character of their metabolism in the enzyme system of liver cells will be investigated too. All this work will create the necessary prerequisites for obtaining a new class of antihypertensive medicines.