RESUMEN
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.
Asunto(s)
Piridinolcarbamato/análogos & derivados , Animales , Arteriosclerosis/tratamiento farmacológico , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Ftalazinas/química , Piridinolcarbamato/química , Piridinolcarbamato/farmacología , ConejosAsunto(s)
Carbamatos/farmacología , Mutágenos , Piridinolcarbamato , Piridinolcarbamato/farmacología , Cromatografía Líquida de Alta Presión , Dimetilsulfóxido/farmacología , Pruebas de Mutagenicidad , Nitritos , Piridinolcarbamato/análogos & derivados , Salmonella typhimurium/efectos de los fármacosRESUMEN
Pyridinol carbamate was nitrosated to the N,N1-dinitroso derivative and the structure was proved by spectroscopic methods, including chemical ionization mass spectroscopy. By the Ames test, the dinitroso derivative showed a significant dose-dependent mutagenic response with Salmonella typhimurium strains TA 1535 and TA 100; the response became more pronounced in the presence of microsomes. As the dosage of N-nitroso pyridinol carbamate increased, the number of revertant colonies also increased. Pyridinol carbamate was not mutagenic.
Asunto(s)
Carbamatos , Mutágenos , Nitrosaminas/farmacología , Piridinolcarbamato , Animales , Carbamatos/análogos & derivados , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Hígado/efectos de los fármacos , Hígado/metabolismo , Piridinolcarbamato/análogos & derivados , Piridinolcarbamato/metabolismo , Piridinolcarbamato/farmacología , RatasRESUMEN
Peripheral atherosclerosis was treated in 178 patients: 90 were given pyridinol carbamate for 2--4 months, 40 pentoxyphylline, 30 cetedil, and 18 received butalamine. in intermittent claudication pyridinol carbamate and trental proved most effective, cetedil (straten) was less effective. The favourable effect of pyridinol carbamate is associated with its action both on the state of microcirculation and on the content of lipids. A significant decrease in the level of blood triglycerides was observed during treatment with pyridinol carbamate. Pentoxyphylline reduced blood viscosity and platelet aggregation in patients with peripheral atherosclerosis but had no effect on the blood lipid content. Cetedil did not reduce blood viscosity although it decreased the aggregation of erythrocytes and inhibited the second phase of platelet aggregation. The objective criterion for the improvement of circulation in the affected extremities was increased tolerance to load, particularly in medication with pyridinol carbamate and trental.