1 The pharmacological profile of valsartan, (S)-N-valeryl-N-([2'-(lH-tetrazol-5-yl) (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg-' daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7 In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1-30 mg kg'. The hypotensive effect persisted up to 12 h after 3 and l0mgkg-' and up to 24h after 30mgkg-'.8 In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan (DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h). 9 These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at the AT,-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive, sodium-depleted primates.

1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity. 4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

Angiotensin I1 (Ang II), an octapeptide formed from the decapeptide angiotensin I by the proteolytic action of angiotensin-converting enzyme (ACE), plays a key role in the regulation of blood pressure and fluid and electrolyte homeostasis (for review see ref. 16). Inhibitors of ACE are used for the treatment of hypertension and congestive heart failure and in patients with left-ventricular dysfunction after myocardial infarction (22,26,27). In the past, attempts to develop Ang I1 receptor antagonists failed because they lack oral activity (25) and have unwanted agonistic properties (24). More recently specific, nonpeptide, orally active Ang 11-receptor antagonists have been developed (1,12,15,20,33,37,41,44) from imidazole derivatives first described by Furukawa et al. ( 1 3). This new class of agents provides selective blockade of the AT,-Ang I1 receptor subtype without interfering with the AT2-receptor subtype. The AT,-receptor subtype is responsible for the well-known effects of Ang 11, such as vasoconstriction, aldosterone and epinephrine release, water intake, and cellular proliferation (6,32,36), whereas the pathophysiological role of the AT2-receptor subtype is not yet well understood (63).Losartan (originally known as DuP 753) was the first orally active antagonist of the AT,-receptor subtype (1 2,32,44,46). The blood pressure-lowering effect of losartan is enhanced by its conversion to the active, hepatically-generated carboxylic acid metabolite, EXP3174 or E3174, which is about 20 times more potent than the parent compound as an AT,-receptor antagonist (47). By contrast, valsartan (originally CGP 48933) is a novel and orally active Ang I1 antagonist that does not require hepatic metabolism (5,lO). It is a highly selective antagonist of Ang 11 at the AT,-receptor subtype and does not possess agonistic properties (5). Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats ( 5 ) , conscious normotensive,

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A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.

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