Peter Dr. Bühlmayer

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype

1 The pharmacological profile of valsartan, (S)‐N‐valeryl‐N‐{[2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐yl]‐methyl}‐valine, a potent, highly selective, and orally active antagonist at the angiotensin II (AII) AT1‐receptor, was studied in vitro and in vivo. 2 Valsartan competed with [125I]‐AII at its specific binding sites in rat aortic smooth muscle cell membranes (AT1‐receptor subtype) with a Ki of 2.38 nm, but was about 30,000 times less active in human myometrial membranes (AT2‐receptor subtype). 3 In rabbit aortic rings incubated for 5 min with valsartan, at concentrations of 2, 20 and 200 nm, the concentration‐response curve of AII was displaced to the right and the maximum response was reduced by 33%, 36% and 40%, respectively. Prolongation of the incubation time with valsartan to 1 h or 3 h, further reduced the maximum response by 48% or 59% (after 20 nm) and by 59% or 60% (after 200 nm) respectively. After 3 h incubation an apparent pKB value of 9.26 was calculated. Contractions induced by noradrenaline, 5‐hydroxytryptamine, or potassium chloride were not affected by valsartan. No agonistic effects were observed in the rabbit aorta at concentrations of valsartan up to 2 μm. 4 In bovine adrenal glomerulosa, valsartan inhibited All‐stimulated aldosterone release without affecting the maximum response (pA2 8.4). 5 In the pithed rat, oral administration of valsartan (10 mg kg−1) shifted the All‐induced pressor response curves to the right, without affecting responses induced by the electrical stimulation of the sympathetic outflow or by noradrenaline. Animals treated with valsartan 24 h before pithing also showed significant inhibition of the response to AII. 6 In conscious, two‐kidney, one‐clip renal hypertensive rats (2K1C), valsartan decreased blood pressure in a dose‐dependent manner after single i.v. or oral administration. The respective ED30 values were 0.06 mg kg−1 (i.v.) and 1.4 mg kg−1 (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−1 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−1. The hypotensive effect persisted up to 12 h after 3 and 10 mg kg−1 and up to 24 h after 30 mg kg−1. 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 AT1‐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.

Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose

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.

Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series

Abstract Starting from the structure of DuP-753 and a 3-dimensional model of the pentapeptide Tyr-Ile-His-Pro-Ile, a series of new and highly potent antagonists has been designed where the imidazole moiety of the Du Pont compound has been replaced by an N-acylated aminoacid residue. VALSARTAN (Ex. 4e CGP48933, (S)-N-Valeryl-N-[2′-(1H-tetrazol-5-yl-)biphenyl-4-yl]methyl-valine), has been selected for clinical investigation.

Syk inhibitors with high potency in presence of blood.

We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).