17β-(3-Furyl)-5β-androstane-3β,14β,17α-triol (PST 2238). A Very Potent Antihypertensive Agent with a Novel Mechanism of Action

Quadri, Luisa; Bianchi, Giuseppe; Cerri, Alberto; Fedrizzi, Giorgio; Ferrari, Paolo; Gobbini, Mauro; Melloni, P.; Sputore, Simona; Torri, Marco Danilo Claudio

doi:10.1021/jm970162e

Cited by 52 publications

(54 citation statements)

References 15 publications

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“…It does not interact `in vitro' with other receptors involved in blood pressure regulation or hormonal steroid control (26) and does not cause any cardiac effect when tested both on isolated cardiac preparations and `in vivo' (28). PST 2238, is a potent antihypertensive compound active both in genetic (27) and ouabain-dependent (26) experimental models of hypertension.…”

Section: Methods and Resultsmentioning

confidence: 99%

“…Following this approach, among more than 800 original molecules, compound PST 2238 has been selected (26)(27)(28) for its ability to selectively displace the ouabain binding from the Na-K ATPase receptor and to be antihypertensive in experimental and genetic models of hypertension in which the above-mentioned alterations are operating.…”

Section: Humansmentioning

confidence: 99%

“…PST 2238 (from 0.1 to 100 sag/kg os), in parallel with its hypotensive effect, antagonizes the ouabaindependent increase in renal Na-K ATPase activity and normalizes it to the level of normotensive saline-treated rats (26). Moreover, PST 2238 is also active as antihypertensive agent in other rat experimental models of volume-dependent hypertension, such as the DOCA+ salt, DOCA+salt+ouabain and reduced renal mass models (28). The selectivity of action of PST 2238 is suggested by the following data: PST 2238 does not affect either blood pressure or renal Na-K ATPase activity in normotensive MNS and normal Sprague Dawley rats (26,27) and does not affect heart rate in any of the animal models studied (26,27).…”

Section: Cell Studiesmentioning

confidence: 99%

“…Therefore, PST 2238 does not display any `diuretic' activity (28). It is devoid of androgenic, estrogenic and corticomimetic effects `in vivo,' does not alter ACTH, prolactin secretion and steroidogenesis `in vitro' and does not affect gastrointestinal motility `in vivo' (28).…”

Section: Cell Studiesmentioning

confidence: 99%

“…Studies of acute and chronic toxicology have been carried out with the results indicating that PST 2238 is welltolerated both in the rat and monkey up to doses 25,000 times higher than the therapeutic dose (28). PST 2238 does not show any mutagenic activity (28); moreover, it is devoid of any adverse effects on reproduction and embryonic development up to an oral dose of 135 mg/kg in rats and 400 mg/kg in rabbits (28).…”

Section: Cell Studiesmentioning

confidence: 99%

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PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

et al. 2000

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A primary renal alteration due to a genetic polymorphism of the cytoskeletal protein adducin associated with an up-regulation of the renal Na-K pump and increased levels of ouabainlike factor (OLF) has been identified as a possible causes of hypertension in Milan rats (MHS). This adducin polymorphism has also been found to be associated with hypertension and the blood pressure changes related to renal Na handling in humans and increased OLF levels have been found in a relevant portion of hypertensive patients. Increased activity and expression of the Na-K pump has also been observed under the following in vitro'and `in vivo' conditions: rat renal cells transfected with the `hypertensive' variant of adducin, as compared with normal cells; normal rat renal cells incubated for 5 days with 10_9 M ouabain and normal rats made hypertensive by a chronic infusion of low doses of ouabain (OS rats). An up-regulation of the Na-K pump seems therefore to be a common biochemical alteration induced both by an adducin polymorphism and/or chronic exposure to low concentrations of ouabain (or OLF). A new antihypertensive compound, PST 2238, that selectively antagonizes the pressor effect and the alteration of the renal Na-K pump induced both by an adducin polymorphism and OLF, is described. The ability of PST 2238 to lower blood pressure and normalize the Na-K pump both in MHS and OS rats suggests that this compound could be useful in the treatment of those forms of essential hypertension in which renal Na-handling alterations are associated with either adducin polymorphisms and/or increased OLF levels.(Hypertens Res 2000; 23 Suppl: S15-S19) Key Words: hypertension, adducin, ouabainlike factor, therapy, pharmacogenomic IntroductionEssential hypertension is a complex disease in which many genetic and environmental factors interact to result in a final blood pressure increase and the risk to develop specific organ complications (mainly at the cardiac, renal, and brain levels) (1, 2). Although the antihypertensive efficacy of different classes of drugs is widely recognized and is similar when large populations are compared, there is much individual variability in the response to a given therapeutical regimen (3). Population surveys have demonstrated that less than 30% of patients are adequately treated. These problems arise primarily from the lack of a complete understanding of the mechanisms that underlay the development of primary hypertension and its organ complications. Therefore, the success of a future new therapy for hypertension will depend upon our understanding of the molecular-genetic mechanisms operating in a subset of patients and the ability of the new drug to correct such a mechanism. A pharmacogenomic approach (4, 5) has been adopted by Prassis sigma-tau to develop a new class of antihypertensive compounds able to lower blood pressure by correcting a specific genetic-molecular mechanism previously demonstrated to be involved both in rat and human hypertension. As a consequence, the

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Section: Methods and Resultsmentioning

confidence: 99%

Section: Humansmentioning

confidence: 99%

Section: Cell Studiesmentioning

confidence: 99%

Section: Cell Studiesmentioning

confidence: 99%

Section: Cell Studiesmentioning

confidence: 99%

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PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

et al. 2000

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Hypertension

2006

Wiley Handbook of Current and Emerging Drug Therapies

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Synthetisch gewonnene Naturstofffragmente in der Wirkstoffentwicklung

Crane¹,

Gademann

2016

Angewandte Chemie

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Die organische Chemie mit ihrer einzigartigen Fähigkeit zur maßgeschneiderten Herstellung von Naturstoff‐Analoga ist ein ausgezeichnetes Mittel, um das volle Potenzial von Naturstoffen bei der Wirkstoffentwicklung auszuschöpfen. In diesem Aufsatz stellen wir eine Strategie vor, die auf von Naturstoffen abgeleiteten Fragmenten basiert, die sich durch eine substanzielle Verringerung des Molekulargewichts, reduzierte strukturelle Komplexität und kürzere Synthesesequenzen zu ihrer Herstellung auszeichnen, während ihre für die Anwendung entscheidenden Eigenschaften wie biochemische Potenz und Selektivität beibehalten oder sogar verstärkt werden. Dies wird anhand von Beispielen aus verschiedenen Stadien des Arzneistoffentwicklungsprozesses bis hin zur klinischen Anwendung erläutert. Darüber hinaus kann die hier beschriebene Strategie durch neuartige Techniken wie die Entwicklung von Antikörper‐Wirkstoff‐Konjugaten oder Genome Mining unterstützt werden. Das Zusammenspiel dieser Ansätze birgt das Potenzial zur Entwicklung der nächsten Generation naturstoffinspirierter Wirkstoffmoleküle.

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17β-(3-Furyl)-5β-androstane-3β,14β,17α-triol (PST 2238). A Very Potent Antihypertensive Agent with a Novel Mechanism of Action

Cited by 52 publications

References 15 publications

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

PST 2238: A New Antihypertensive Compound that Modulates the Na-K Pump ‘in Vivo’ and ‘in Vitro’

Hypertension

Synthetisch gewonnene Naturstofffragmente in der Wirkstoffentwicklung

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