title: Studies on scavenger receptor inhibitors. Part 1: synthesis and structure-activity relationships of novel derivatives of sulfatides.
abstract: Scavenger receptors have been proven to be implicated in the formation of atherosclerotic lesions. A series of novel derivatives of sulfatides were synthesized, and their inhibitory activities against incorporation of DiI-acetyl-LDL into macrophages were evaluated in order to clarify the structure-activity relationships of sulfatides as a scavenger receptor inhibitor and find out novel inhibitors with synthetic easiness. The chemical modification of the substructures of sulfatides led to the establishment of the following structure-activity relationships; (1) the ceramide moiety can be replaced with another structure bearing two long chains, (2) the galactose moiety can be replaced with another structure or be deleted without a large decrease in the inhibitory activity, (3) the sulfate moiety was crucial, and it was the most preferable functional group for a potent inhibitory activity. The inhibitory activity of (S)-2-octadecanoylamino-2-tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) against incorporation of DiI-acetyl-LDL into macrophages was proven to be based on the inhibition against the binding of acetyl-LDL to the surface of macrophages. We discovered novel scavenger receptor inhibitors with synthetic easiness, such as (S)-2-octadecanoylamino-2-(tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) and 2-octadecanoylamino-1-(octadecanoylaminomethyl)ethyl sulfate sodium salt (13q).
authors.affiliation: R & D Laboratories, Nippon Organon K.K., 1-5-90 Tomobuchi-cho, Miyakojima-ku, 534-0016 Osaka, Japan. k.yoshizumi@organon.nhe.akzonobel.nl
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yoshiizumi
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakajima
authors.forename: Rika
authors.initials: R
authors.lastname: Dobashi
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Nishimura
authors.forename: Shoji
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000493:pharmacokinetics; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013329:Structure-Activity Relationship; D013433:Sulfoglycosphingolipids / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013433:Sulfoglycosphingolipids