NO-Sartans:  A New Class of Pharmacodynamic Hybrids as Cardiovascular Drugs

Breschi, Maria Cristina; Calderone, Vincenzo; Digiacomo, Maria; Martelli, Alma; Martinotti, Enrica; Minutolo, Filippo; Rapposelli, Simona; Balsamo, Aldo

doi:10.1021/jm049681p

Cited by 44 publications

(36 citation statements)

References 32 publications

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“…83 A group from the University of Pisa in Italy has described the synthesis and characterization of NO-donor analogs of losartan and its active metabolite EXP-3174. 84,85 The bifunctional nature of the compounds was assessed using in vitro organ bath preparations of rat endothelium-denuded aortic rings. ARB-NO hybrids mediated concentration-dependent relaxation of aortic rings pre-contracted with KCl, which was blocked in the presence of ODQ, an inhibitor of guanylate cyclase, showing the activation of the NO-cGMP pathway by the compound.…”

Section: Next Generation Arbs That Are No Donorsmentioning

confidence: 99%

“…A group from the China Pharmaceutical University in Nanjing, China, has explored NO-releasing derivatives of telmisartan using an approach similar to that of Breschi et al [84][85][86] The lead compound WB1106 was found to have dual activity in isolated rat aortic preparations and significantly reduced angiotensin II-mediated pressor responses in normotensive rats. WB1106 lowered blood pressure in spontaneously hypertensive rats to the same extent as telmisartan, but, in contrast to telmisartan, increased aortic cGMP levels, with similar magnitude as the ACE inhibitor, fosinopril.…”

Section: Next Generation Arbs That Are No Donorsmentioning

confidence: 99%

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Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the reninangiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT 1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin-angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT 1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic risk through multiple mechanisms that go beyond just inhibition of the renin-angiotensin system and (2) describe specific examples of next generation ARBs in development that are intended to do more than simply block AT 1 receptors.

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Section: Next Generation Arbs That Are No Donorsmentioning

confidence: 99%

Section: Next Generation Arbs That Are No Donorsmentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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“…Indeed, NO-releasing losartan and NO-releasing telmisartan have been synthesized and demonstrated to have superior cardiovascular effects when compared with those of the original ARBs in ex vivo and in vivo preclinical studies. [7][8][9] Interestingly, however, clinical trials have not yet been reported for NO-releasing ARBs.…”

Section: Article P656mentioning

confidence: 99%

Next Generation ARBs

et al. 2015

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“…In the thriving panorama of cardiovascular NO-releasing drugs, a new class of potential antihypertensive agents, NOSartans, (pharmacodynamic hybrids which show the dual profile of a typical AT1-antagonist and of a slow NO-donor) has been recently reported [205]. Like ACE-inhibitors, sartans, such as losartan, act on the RAS, but not interfering with the ACE; in fact, their mechanism of action consists of the antagonism of the angiotensin II receptor AT1.…”

Section: No-sartansmentioning

confidence: 99%

NO-Releasing Hybrids of Cardiovascular Drugs

Martelli

Rapposelli²,

Calderone³

2006

CMC

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Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.

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NO-Sartans: A New Class of Pharmacodynamic Hybrids as Cardiovascular Drugs

Cited by 44 publications

References 32 publications

Next generation multifunctional angiotensin receptor blockers

Next generation multifunctional angiotensin receptor blockers

Next Generation ARBs

NO-Releasing Hybrids of Cardiovascular Drugs

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