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The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, Po0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; Po0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

Studies in laboratory animals suggest that altered nitric oxide (NO) production may be associated with salt sensitivity. In this investigation we determined whether the endogenous NO production was altered in salt-sensitive human subjects when salt intake was changed. Salt sensitivity was assessed from the magnitude of the blood pressure (BP) lowering obtained when the salt intake was reduced from high to a low intake. The combined urinary excretion of nitrites and nitrates, the major metabolites of NO, was employed as an index of endogenous NO production. Salt-sensitive subjects (n = 23) were older, heavier, and had greater waist-to-hip ratios and higher baseline BP than salt-resistant individuals (n = 25). In salt-sensitive subjects, mean blood pressure (MBP) decreased 11.8+/-0.7 mm Hg, and NO metabolite excretion increased from 823+/-102 to 1530+/-148 mmol/24 h, when salt intake was reduced from 316 to 28 micromol/day. NO metabolite excretion was 45% lower during high salt (0.66+/-0.1 micromol/mg creatinine) than during low salt intake (1.12+/-0.1 micromol/mg creatinine) (P < .001). In contrast, when salt intake was reduced, salt-resistant subjects exhibited no significant mean changes in BP or NO metabolite excretion. During low salt intake, NO metabolite excretion (micromol/ day) was significantly higher in salt-sensitive individuals. The magnitude of decrease of systolic blood pressure, diastolic blood pressure, or MBP induced by reducing salt intake was not related to the increase in urinary excretion of NO metabolite levels (r2 = 0.009; P = .66). In summary, to the extent that urinary NO metabolite levels reflect the activity of the endogenous NO system, our results support the view that salt sensitivity may in part be determined by an inability to increase or to sustain NO production in response to high salt. Insufficient NO production during high salt may in turn lead to altered pressure-natriuresis relationships and to an increase in BP. The possibility that the increase in BP induced by high salt intake in salt-sensitive individuals could be the key factor in reducing NO metabolite levels can not be ruled out.