Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl] cytosine.

The synthesis and antiviral evaluation of 21 prodrugs of 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl ] cytosine 1 is reported. Cytosine N4-imine analogues were prepared by condensation of 1 with selected formamide dimethyl acetals. Amino acid substituted prodrugs were prepared from 1 or imine prodrug 2 by coupling with either N-tert-butoxycarbonyl (t-Boc)-L-valine or N-t-Boc-L- phenylalanine in the presence of dicyclohexycarbodiimide (DCC) and 4-dimethylaminopyridine (4-DMAP). Deprotection of the t-Boc protecting group was achieved with trifluoroacetic acid (TFAA) in methylene chloride. Cytosine N4-amide analogues were prepared by reaction of 1 with appropriate anhydrides in aqueous dioxane. Triacylated analogue 22 was prepared by reaction of 1 with four equivalents of benzoyl chloride in pyridine. Prodrugs were evaluated for activity against duck hepatitis B virus, herpes simplex virus types 1 and 2, human cytomegalovirus, and human immunodeficiency virus. A number of analogues were found comparable in activity to 1 with the cytosine N4-imine series more active than the amino acid substituted and cytosine N4-amide prodrugs. Slight to moderate cellular toxicity was observed with some analogues.

Incidence and pathophysiologic significance of infected carotid artery plaque.

It is unknown whether an association exists between infectious microorganisms and atherosclerosis. Eighty consecutive patients undergoing carotid endarterectomy were studied to detect for bacterial or virus infections in removed carotid atherosclerotic plaques. Twenty-one patients (25%) were found to have positive cultures for bacteria of the carotid plaques. Three patients (4%) did not have bacterial contamination of controlled cultures of the skin. Of these three patients, two grew diptheroids and one grew staphylococcus. The control cultures of the skin demonstrated that 25 patients (31%) grew diphtheroids and 29 (36%) grew staphylococcus. Five patients grew both organisms. There was no evidence of colonization within the atheromatous plaque material in histologic studies of the three patients that had positive cultures of their plaque. All viral cultures were negative. The positive carotid cultures found were most likely due to contamination from the skin. This study demonstrates the unlikelihood of bacterial or virus infections as either an etiologic or a pathogenetic factor in carotid artery atherogenesis.

Pharmacological characterization of LY293284: A 5-HT1A receptor agonist with high potency and selectivity.

(-)-LY293284, (-)-4R-6-acetyl-4-(di-n-propylamino)1,3,4,5- tetrahydrobenz[c,d]indole, is a conformationally restricted tryptamine derivative with an acetyl group serving as a protophilic substitution for the hydroxyl in serotonin (5-HT). In ligand displacement studies, LY293284 had a Ki of 0.07 nM for the 5-HT1A receptor but no affinity for other monoaminergic receptors within 3 orders of magnitude. LY293284 was evaluated in in vivo models, which have been used as markers for presynaptic and postsynaptic 5-HT1A receptor activity. LY293284 decreased hypothalamic 5-hydroxyindoleacetic acid levels (ED50, 2.9 micrograms/kg s.c.) and dorsal raphe serotonergic neuron firing rate (ED50, 0.08 micrograms/kg s.c.), which are accepted indices of presynaptic activity. LY293284 also induced a reduction in body temperature in rats (ED50, 3.6 micrograms/kg s.c.), which was blocked by pretreatment with (+/-)-pindolol. Hypothermic responses of rats to 5-HT1A agonists have had both pre- and postsynaptic characteristics in previous studies. The ED50 values for 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in these tests were 15 to 45 times higher than those observed for LY293284. In models for postsynaptic activity, the ED50 for LY293284 for elevating serum corticosterone levels was 9.7 micrograms/kg s.c. and the minimum effective doses to induce lower lip retraction and flat posture were 3 micrograms/kg s.c. For comparison, the same indices obtained for 8-OH-DPAT were 222.4 and 100 micrograms/kg, respectively. The 5-HT syndrome responses induced by LY293284 were also attenuated by pretreatment with (+/-)-pindolol. LY293284 was 10 times more potent than 8-OH-DPAT in a drug discrimination test that used pigeons trained to identify 8-OH-DPAT. In sexual behavior tests with male rats, LY293284 induced a maximal reduction in ejaculatory latency at 0.01 micrograms/kg s.c., which was approximately 10 times higher potency than 8-OH-DPAT. In the pigeon conflict model for anxiolytic activity, LY293284 was 100 times more potent than 8-OH-DPAT in increasing punished responding. In the rat forced swim model for antidepressant-like activity, LY293284 was 30 and 35 times more potent than 8-OH-DPAT in decreasing immobility time and defecation rate. These studies have demonstrated that LY293284 is a highly selective and extremely potent 5-HT1A receptor agonist and represents a useful pharmacological tool for studying 5-HT1A receptor-mediated effects.

Evaluation of a novel antihypertensive agent, LY127210, in anesthetized and conscious spontaneously hypertensive rats.

LY127210 (7,8-dimethoxy-1H-3-benzazepin-2-amine, hydrochloride) is a novel peripheral arterial vasodilator that reduces mean arterial blood pressure in anesthetized and conscious spontaneously hypertensive rats by all conventional routes of administration. The antihypertensive activity of LY127210 results predominantly from a decrease in total peripheral vascular resistance, and the degree of reflex tachycardia produced by LY127210 in conscious spontaneously hypertensive rats is significantly less than that produced by hydralazine at equivalent antihypertensive doses. The relative lack of reflex tachycardia produced by LY127210 appears to result from a direct bradycardic effect of the compound that occurs at the level of the myocardium at doses similar to those required to produce peripheral arteriolar vasodilation. It is proposed that the direct bradycardic effect of LY127210 serves to offset, at least in part, the tachycardia resulting from reflex stimulation of sympathetic outflow that occurs upon activation of the baroreflex loop as blood pressure is lowered. The results indicate that LY127210 may provide adequate control of blood pressure and may not require the concomitant administration of a beta-adrenoceptor antagonist to control reflex tachycardia, as is commonly necessary with hydralazine.

Synthesis of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine. Inhibitors of rhinovirus multiplication.

The synthesis and antirhinovirus activity of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine (4 and 5) are reported. The structural assignments of 4 and 5 are based upon 13C NMR spectra of both isomers and also X-ray analysis of 5. The anti-isomer 5 was more potent than the syn-isomer 4 when compared as an inhibitor of rhinovirus multiplication in vitro. Both isomers inhibited multiplication of 15 different serotypes of rhinovirus.