Preparation and evaluation of the antiatherosclerotic activity of unsymmetrical pyridinolcarbamates.

Abstract

To discover a new and powerful antiathersclerotic agent which can regulate the transendotherial infiltration of very low density lipoprotein (VLDL), LDL, and another type of atherogenics, various kinds of unsymmetrical pyridinolcarbamate derivatives were prepared. The syntheses were started from partial reduction of diethyl dipicolinate with sodium borohydride. The resulted hydroxymethyl group was converted to N-methylcarbamate by a general procedure, and the remaining 6-ethoxycarbonyl group was modified to various kinds of structures. Most of the test compounds showed significant inhibition on edematous arterial reaction (EAR), which closely resembles to an early stage of atherosclerosis, in rabbit aorta in vivo. Among the compounds tested, we found the novel and most potent inhibitor, 2-methylaminomethyl-6-(N-methylcarbamoyloxymethyl) pyridine (13) coded as SHI-355, which inhibited the formation of edematous change on EAR less than 47%. This potency is much more efficient than those of pyridinolcarbamate (1) (83%) and phthalazinol (22) (64%). Furthermore, the morphological differences on the way of inhibition on edematous changes were not observed among the results of the test compounds.