Renin inhibitory activity

Further optimization of the P3 substituent revealed that 3,4-bis-alkoxy substitution of the phenyl ring improved potency, with the optimal combination 3-(3-methoxypropoxy) and 4-methoxy (7, Table 2). Compound 7 exhibits exceptional renin inhibitory activity in both buffer and plasma and showed moderate in vivo activity in telemetered, sodium-depleted marmosets, with peak reduction of mean arterial pressure of 9 mm Hg and an 8-h duration of action.20 An X-ray co-crystal structure of compound 7 with recombinant human renin established that the methoxypropoxy sidechain occupies a narrow nonsubstrate pocket, termed S3sp. The importance of terminal methoxy group is... 

Table I. Renin Inhibitory Activity of the Perfluoroalkyl Compounds...

Table n.Renin Inhibitory Activity of Compounds Containing Statine... 

The angiotensin I-converting enzyme (ACE) participates in regulating blood pressure in the renin-angiotensin system. The inhibitors such as captopril (Suetsuna and Chen, 2001) and enalapril (Sawayama et ah, 1990) have been used as antih)/pertensive drugs. The ACE-inhibitory activity of various source have studied, and it was found that some ACE-inhibitory peptides were produced by enzymatic digestion of various marine food proteins, including tuna muscle (Kohama et al., 1991 Qndetti, 1977), sardine muscle (Suetsima et al., 1991), dried bonito (Yokoyama et ah, 1992), dried-salted fish (Astawan et ah, 1995), fish sauce (Okamoto et al, 1995), and fish water-soluble protein (Wako et ah, 1999). 

Pharmacology The proposed mechanism of action of methyidopa is probably due to the drug s metabolism to alpha-methyl norepinephrine, which lowers arterial pressure by the stimulation of central inhibitory -adrenergic receptors, false neurotransmission or reduction of plasma renin activity. 

Mechanism of Action An antihypertensive agent that stimulates central inhibitory alpha-adrenergic receptors, lowers arterial pressure, and reduces plasma renin activity. Therapeutic Effect Reduces BP. 

In the brain, methyldopa is enzymatically decarboxy-lated to a-methyldopamine, which undergoes subsequent enzymatic conversion, via hydroxylation, to a-methylnorepinephrine, an a-adrenergic agonist. Stimulation of central inhibitory a-adrenergic receptors causes a decrease in sympathetic outflow manifested as a decrease in blood pressure. A decrease in plasma renin activity may also play a role in methyldopa s hypotensive effects. 

Other modifications of the difluoroketone as renin inhibitors are shown in Table HI. The retroamide-type analogue of difluorostatone (23) is illustrated as in compound XIV which shows reasonable inhibitory potency with an IC value of 25 nM. Interestingly, the shorter congener, compound XV, is nearly 10 times more active. The sulfone analogue (77) XVII is also a potent inhibitor with an IC value of 1 nM. As expected, the corresponding hydroxy analogue XVI is not as active. 

This active metaboiite of methyidopa decreases total peripheral resistance, with little change in cardiac output and heart rate, through its stimulation of central inhibitory a2-adrenoceptors. A reduction of plasma renin activity also may contribute to the hypotensive action of methyidopa. Postural hypotension and sodium and water retention also are effects related to a reduction in blood pressure. If a diuretic is not administered concurrently with methyidopa, tolerance to the antihypertensive effect of the methyidopa during prolonged therapy can result. 

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