Synthesis of lysophosphatidylethanolamine analogs that inhibit renin activity.
A series of lysophosphatidylethanolamine analogs containing saturated and methylene-interrupted cis-olefinic fatty chains was synthesized by phosphorylation and phosphonylation of respective fatty alcohols. Arachidonyl- and linolenylphosphorylethanolamines (12, 13), arachidonyl (2-phthalimidoethyl)phosphonate (17), and arachidonyl (2-aminoethyl)phosphonate (18) were found to be effective inhibitors of the renin-renin substrate reaction in vitro; lysophosphatidylethanolamine analogs 14-16 of lesser unsaturation were either weakly active or inactive. In a preliminary study, intramuscular administration of 25 mg/kg/day of arachidonyl (2-aminoethyl)phosphonate (18) to the hypertensive rat caused pronounced reduction (50 mm) in blood pressure within 3 days; upon continued dosage (15 mg/kg/day) of 18 for an additional 4 days, plasma renin activity was found to be 16 ng/0.1 ml/15 hr as compared with 69 ng/0.1 ml/15 hr before initial drug administration. Arachidonic acid (3), arachidonyl alcohol (8), and several corresponding tetraenoid ester, amide, mesylate, and glyceryl ether derivatives (4-7, 10, 11), that are not phosphate or phosphonate esters, were found to exhibit negligible or modest inhibition of renin activity in vitro.
D000804:Angiotensin II / Q000096:biosynthesis; D000808:Angiotensinogen / Q000037:antagonists & inhibitors / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004285:Dogs; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D008246:Lysophospholipids; D010714:Phosphatidylethanolamines / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000804:Angiotensin II; D000808:Angiotensinogen; D008246:Lysophospholipids; D010714:Phosphatidylethanolamines; D012083:Renin; D000092502:Renin Inhibitors; C008301:lysophosphatidylethanolamine