Dual Metalloprotease Inhibitors:  Mercaptoacetyl-Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

Robl, Jeffrey A.; Sun, Chuanyu; Stevenson, Jay; Ryono, Denis E.; Simpkins, Ligaya M.; Cimarusti, Maria P.; Dejneka, Tamara; Slusarchyk, William A.; Chao, Sam; Stratton, L; Misra, Raj N.; Bednarz, Mark S.; Asaad, Magdi M.; Cheung, H.S.; Abboa-Offei, B E; Smith, Patricia L.; Mathers, Parker D.; Fox, Maxine; Schaeffer, Thomas; Seymour, and Andrea A.; Trippodo, N. C.

doi:10.1021/jm970041e

Cited by 201 publications

(123 citation statements)

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“…Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4).…”

mentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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mentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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“…compound omapatrilat (Graul et al, 1999;Robl et al, 1997;Tabrizchi, 2001). As part of our studies of cyclic 1,3-thiaza-4-one compounds, we report the synthesis and structure of the novel title compound.…”

Section: Methodsmentioning

confidence: 99%

“…For preparation of various heterocycles using imines and T3P, see: Unsworth et al (2013). For omapatrilat, see: Graul et al (1999); Robl et al (1997); Tabrizchi (2001).…”

Section: Related Literaturementioning

confidence: 99%

6,7-Diphenyl-5-thia-7-azaspiro[2.6]nonan-8-one

Yennawar

Silverberg

2013

Acta Cryst E

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Key indicators: single-crystal X-ray study; T = 298 K; mean (C-C) = 0.003 Å; R factor = 0.047; wR factor = 0.134; data-to-parameter ratio = 17.9.The asymmetric unit of the title compound, C 19 H 19 NOS, contains two independent molecules (A and B), in both of which the 1,3-thiazepan-4-one ring adopts a chair-type conformation. The dihedral angles between the two phenyl rings are 65.28 (8) and 60.31 (9) for molecules A and B, respectively. In the crystal, molecules are linked by weak C-HÁ Á ÁO interactions, resulting in a three-dimensional network. Related literature

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“…47 Attenuation of the RAAS via ACE inhibition has proven cardiac and mortality benefits in HF patients, 3,48 and both inhibition of neprilysin and ACE leads to greater cardiorenal benefits (eg, improved natriuresis and diuresis and lower levels of Ang II and aldosterone) in preclinical models of HF, likely via increased levels of NPs and other vasodilating peptides, such as bradykinin, while simultaneously preventing the conversion of Ang I to Ang II. 49e52 In a postemyocardial infarction (MI) rodent model, omapatrilat decreased myocardial fibrosis compared with placebo and decreased LV hypertrophy compared with captopril.…”

Section: Omapatrilatmentioning

confidence: 99%

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Buggey

Mentz

DeVore

et al. 2015

Journal of Cardiac Failure

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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

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Dual Metalloprotease Inhibitors: Mercaptoacetyl-Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

Cited by 201 publications

References 17 publications

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Physiologic Consequences of Vasopeptidase Inhibition in Humans

6,7-Diphenyl-5-thia-7-azaspiro[2.6]nonan-8-one

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

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