Maria A. Palomo

Phosphoramidon Blocks the Pressor Activity of Big Endothelin[1–39] and Lowers Blood Pressure in Spontaneously Hypertensive Rats

In porcine aortic endothelial cells, the 21-amino acid peptide endothelin-1 (ET-1) is formed from a 39-amino acid intermediate big endothelin (big ET) by a putative endothelin-converting enzyme (ECE) that cleaves the 39-mer at the Trp21-Val22 bond. Because big ET has less than 1% of the contractile activity of ET-1, inhibition of ECE should effectively block the biological effects of big ET. Big ET injected intravenously into anesthetized rats produces a sustained pressor response that presumably is due to conversion of big ET to ET-1 by ECE. We determined the type of protease activity responsible for this conversion by evaluating the effectiveness of protease inhibitors in blocking the pressor response to big ET in ganglion-blocked anesthetized rats. The serine protease inhibitor leupeptin, the cysteinyl protease inhibitor E-64, and the metalloprotease inhibitors captopril and kelatorphan were ineffective at blocking the pressor response to big ET. However, the metalloprotease inhibitors phosphoramidon and thiorphan both dose-dependently inhibited the pressor response to big ET, although phosphoramidon was substantially more potent than thiorphan. None of the inhibitors blocked the pressor response to ET-1 and none had any effect on blood pressure when administered alone as an i.v. bolus to the ganglion-blocked anesthetized rat. However, phosphoramidon infused intravenously at 20 mg/kg/h for 4 h lowered the mean arterial pressure (MAP) in conscious spontaneously hypertensive rats (SHRs) whereas kelatorphan at the same dose did not. Our results suggest that ECE is a novel metalloprotease and that ECE inhibitors could have therapeutic potential for the treatment of hypertension.

N1-sterically hindered 2H-imidazol-2-one angiotensin II receptor antagonists: The conversion of surmountable antagonists to insurmountable antagonists

Abstract The surmountable (competitive) N 1 -(2-methylphenyl)-2H-imidazol-2-one angiotensin II receptor antagonist SC-54628 is converted to an insurmountable (noncompetitive) antagonist SC-54629 by the addition of a methyl group at the 6-position of the phenyl ring.

Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist

Summary We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AH) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT, receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AH. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.

1H-1,2,4-triazole angiotensin II receptor antagonists: N-phenylpyridinylmethyl and N-pyridinylphenylmethyl analogs of SC-50560

Abstract Substituting nitrogen for carbon in the pyridinylphenylmethyl analogs of SC-50560 proved to be detrimental, however, the two phenylpyridinylmethyl analogs of SC-50560 retained their potencies. Of these two analogs, SC-52458 was found to have superior in vivo properties.

Synthesis and biological activity of N-terminus modified [Ile8] angiotensin II analogues

Abstract Semi-peptidic analogues of the angiotensin II (AII) antagonist [Ile8] AII have been prepared by the solid phase method and, for some steps, by synthesis in solution. In the modified analogues 4–15, the N-terminal di- or tripeptidic fragments (Asp-Arg or Asp-Arg-Val) in [Ile8]AII was replaced by non-peptidic moieties featuring amino or guanidino groups as substituent of simple alkyl spacers of various lengths. The compounds synthesized have been tested for their ability to produce an AII-like contraction and/or to inhibit AII-induced contractions in isolated rabbit aortae. All of them were found devoid of agonistic activity and most retained significant antagonistic activity in this assay. Analogue 5 antagonized AII-induced blood pressure effect in the anesthetized rat when infused at 30 μg/kg/min. The structure-activity relationships for these compounds are discussed.

Effects of SC-52458, an Angiotensin AT1 Receptor Antagonist, in the Dog

We have previously reported on the basic pharmacologic properties of SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), a novel angiotensin (AII) receptor antagonist that binds potently to AT1 receptors in rat adrenal cortex and blocks AII-mediated contraction in isolated rabbit aorta. In the present study, the ability of SC-52458 to block AII pressor responses in conscious dogs was measured. In addition, we determined whether SC-52458 lowered mean arterial pressure in dogs with 2 kidney/1 clip renal hypertension when given daily for 4 days. In conscious, normotensive dogs, SC-52458 at 30 mg/kg orally, blocked the pressor response to AII (50 ng/kg, intravenously) with maximal inhibition (91%) observed 2 h after dosing. Plasma concentrations of SC-52458 measured by HPLC also were highest at the 2-h time point. After 24 h, the AII pressor response remained inhibited (by 35%) and SC-52458 was still measurable in plasma from treated dogs. In dogs made hypertensive by constriction of the left renal artery, SC-52458 lowered mean arterial pressure compared to vehicle treatment although heart rate was not different in the two groups. The maximal blood pressure lowering achieved with SC-52458 was similar to the maximal effect observed with the angiotensin converting enzyme inhibitor lisinopril. We conclude that SC-52458 blocks AII mediated pressor responses in normotensive, conscious dogs and SC-52458 is an efficacious antihypertensive agent in dogs with 2 kidney/1 clip renal hypertension.