"Scaffold-Hopping" by Topological Pharmacophore Search: A Contribution to Virtual Screening.

A chemically advanced template search (CATS) based on topological pharmacophore models has been developed as a technique for virtual screening. This technique has successfully identified novel potent Ca(2+) antagonists (such as 2) that have a similar activity to 1 (a known T-channel blocking agent) in a library of several hundred thousand compounds on the basis of a correlation vector representation.

Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm.

Endothelin (ET) receptor antagonists are of great potential clinical interest for the treatment pathological conditions associated with vasospasm, such as subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed for high water solubility. Ro 61-1790 [5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range. It has a approximately 1000-fold selectivity for the ETA vs. the ETB receptor as assessed on functional assays (e.g., ET-1-induced inositol-1,4, 5-triphosphate release or ET-1-induced intracellular calcium mobilization). Ro 61-1790 also had a high functional potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ETA receptors; pA2 = 9.5) or by sarafotoxin S6c on rat trachea (ETB receptors; pA2 = 6.4). In vivo, Ro 61-1790 inhibited the pressor effect of big ET-1 in pithed rats with an ID50 value of 0.05 mg/kg. Intravenous bolus of Ro 61-1790 induced a long-lasting antihypertensive effect in deoxycorticosterone acetate salt rats instrumented with telemetry. In a double-hemorrhage canine model of SAH, Ro 61-1790 both prevented and reversed cerebral vasospasm in a dose-dependent manner. In an established cerebral vasospasm, 3 mg/kg Ro 61-1790 i.v. was half as efficacious as intrabasilar papaverine. Ro 61-1790 (20 mg/kg/day) totally prevented the occurrence of vasospasm. In summary, these data demonstrate that Ro 61-1790 is a potent and selective ETA receptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.

In vitro characterisation of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor.

We describe here Ro 46-8443, the first non-peptide endothelin ETB receptor selective antagonist. It displays up to 2000-fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition. The observed parallel rightward shift of concentration-response curves with different antagonist concentrations is consistent with a competitive binding mode. Since R0 46-8443 selectively inhibits ETB receptor mediated responses, it is a valuable tool for clarifying the role of ETB receptors in pathology.

Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist.

The authors describe here the pharmacological properties of bosentan, a new nonpeptide mixed antagonist of endothelin (ET) receptors, obtained by structural optimization of the less potent Ro 46-2005 [Ro 46-2005 (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-4-pyrimidinyl ]-benzenesulfonamide]. Bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4-yl]-benzenesulfonamide) competitively antagonized the specific binding of [125I]-labeled ET-1 on human smooth muscle cells (ETA receptors) with a Ki of 4.7 nM and on human placenta (ETB receptors) with a Ki of 95 nM. It also inhibited the binding of selective ETB ligands on porcine trachea. Contractions induced by ET-1 in isolated rat aorta (ETA) and by the selective ETB agonist sarafotoxin S6C in rat trachea were competitively inhibited by bosentan (pA2 = 7.2 and 6.0, respectively), as was the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery (pA2 = 6.7). The binding of 40 other peptides, prostaglandins, ions and neurotransmitters was not significantly affected by bosentan, which shows its specificity for ET receptors. In vivo, bosentan inhibited the pressor response to big ET-1 both after i.v. and oral administration, with a long duration of action and no intrinsic agonist activity. It also inhibited the depressor and pressor effect of ET-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally active antagonist of ET receptors described so far. Its pharmacological profile makes bosentan a potentially useful drug in the management of clinical disorders associated with vasoconstriction.

Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist.

Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized towards the basolateral side, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active nonpeptide antagonist of endothelin receptors, Ro 46-2005.

Ro 42-5892 is a potent orally active renin inhibitor in primates.

The goal of the present study was to characterize the new renin inhibitor Ro 42-5892 in vitro and in vivo. In vitro, Ro 42-5892 inhibited purified human renin and human plasma renin specifically with an IC50 of 0.7 nM and 0.8 nM, respectively. In vivo, Ro 42-5892 reduced mean arterial blood pressure in sodium-depleted marmosets and squirrel monkeys with as low a dose as 0.1 mg/kg orally. Higher doses reduced pressure by 30-35 mm Hg in both species. The duration of blood pressure decrease with 3 mg/kg orally was more than 24 hours. Maximal changes of plasma renin activity, immunoreactive angiotensin I, and immunoreactive angiotensin II were observed at 15 minutes. Renin was reduced by 74 +/- 31%, angiotensin I by 85 +/- 14%, angiotensin II by 89 +/- 17%, and immunoreactive active renin was increased by 70 +/- 39%. However, unlike pressure, these maximal effects were only transient with complete recovery of renin at 60 minutes under still reduced levels of angiotensin I (61 +/- 24%) and angiotensin II (71 +/- 38%) and increased concentrations of active renin (86 +/- 30%). The blood pressure lowering was due to specific renin inhibition as exemplified by the influence of the kidney, sodium status, species, or stereoselectivity. Moreover, the reduction of arterial blood pressure was similar to the action of the angiotensin converting enzyme inhibitor cilazapril and was not associated with reflex tachycardia in contrast to the pure vasodilator minoxidil. We conclude that Ro 42-5892 is a potent orally active renin inhibitor acting mainly by inhibition of renin in an extraplasmatic compartment.