TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model

Hara, Tomoya; Nishimura, Satoshi; Yamamoto, Toshihiro; Kajimoto, Yumiko; Kusumoto, Keiji; Kanagawa, Ray; Ikeda, Shota; Nishimoto, Tetsuya

doi:10.1371/journal.pone.0202176

Cited by 6 publications

(10 citation statements)

References 48 publications

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“…In early human clinical trials, doses of 5–200 mg of TAK‐272 were tested in healthy subjects. TAK‐272 at 5 mg per person demonstrated potent and prolonged renin inhibition over 24 h, which was comparable to the effects of 10 mg·kg −1 in triple‐tg mice and the effects of 300 mg·kg −1 in CSQ‐tg mice, as shown in our previous study . This indicates that the effective dose of TAK‐272 in triple‐tg mice was much closer to a clinical dose in humans, than in CSQ‐tg mice.…”

Section: Discussionsupporting

confidence: 82%

“…In CSQ‐tg mice, 300 mg·kg −1 of TAK‐272 was required to exert an antihypertrophic effect shown as decrease in LV weight in the present study. Our previous study also indicated that TAK‐272 at 300 mg·kg −1 improved the survival rate of CSQ‐tg mice, but this effect was not significant at 100 mg·kg −1 . On the other hand, we demonstrated that a much lower dose of TAK‐272 (10 mg·kg −1 ) significantly improved cardiac hypertrophy and mortality in triple‐tg mice in the present study.…”

Section: Discussionsupporting

confidence: 47%

“…The survival rate of male CSQ‐tg ( n = 43) and triple‐tg mice ( n = 41) was monitored for 68 days. As a humane endpoint, the animals were euthanized in cases where rectal temperature dropped (below 29 °C), body weight decreased severely, or extremely low activity was observed according to prespecified criteria . Body weight was measured twice a week, and rectal temperature was also measured once daily until the end of the study.…”

Section: Methodsmentioning

confidence: 99%

“…For TAK‐272 as well as other renin inhibitors optimized for human renin, generally high concentrations of the drugs are needed to exert inhibitory effects on rodent renin due to species differences in the amino acid sequence in the catalytic domain of renin . In fact, the renin inhibitory activity of TAK‐272 in mice is 25 times weaker than that in humans . In addition, human renin cannot cleave rodent angiotensinogen efficiently, and vice versa .…”

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confidence: 99%

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Development of a novel murine heart failure model overexpressing human renin and angiotensinogen

et al. 2020

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Renin is the rate‐limiting enzyme of the renin–angiotensin system cascade, which drives the pathophysiological progression of heart failure. Species differences in the amino acid sequence of the catalytic domain of renin limit evaluations of the potency and efficacy of human renin inhibitors in animal models, and a high dose of inhibitors is usually needed to show its organ‐protective effects in rodents. In the present study, we developed a novel murine heart failure model (triple‐tg) to enable us to evaluate the cardioprotective effect of renin inhibitors at more relevant doses for humans, by cross‐breeding calsequestrin transgenic (CSQ‐tg) mice with human renin and human angiotensinogen double‐transgenic mice. The triple‐tg mice exhibited increased plasma renin activity, worsened cardiac hypertrophy, and higher mortality compared to CSQ‐tg mice. Triple‐tg mice treated with 10 mg·kg−1 of TAK‐272 (imarikiren/SCO‐272), an orally active direct renin inhibitor, exhibited improvements in heart failure phenotypes, such as cardiac hypertrophy and survival rate; however, a dose of 300 mg·kg−1 was required to improve symptoms in CSQ‐tg mice. Our results suggest that this newly generated triple‐tg heart failure model is useful to evaluate the cardioprotective effects of human renin inhibitors at clinically relevant doses, thereby minimizing the concerns of off‐target effects related to much higher drug exposure than that achieved in clinical study.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 47%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Development of a novel murine heart failure model overexpressing human renin and angiotensinogen

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“…52,53 Additionally, they showed cardioprotective activity. 54 Plexxikon: Designed tetrahydroquinoline derivatives with an IC 50 < 10 µM for renin inhibition (Fig. 15).…”

Section: K Ramya Et Al Bioorganic and Medicinal Chemistry XXX (Xxxx)mentioning

confidence: 99%

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Ramya

Suresh

Kumar

et al. 2020

Bioorganic & Medicinal Chemistry

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Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin-angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

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Current and emerging drug targets in heart failure treatment

et al. 2021

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After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin–angiotensin–aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.

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TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model

Cited by 6 publications

References 48 publications

Development of a novel murine heart failure model overexpressing human renin and angiotensinogen

Development of a novel murine heart failure model overexpressing human renin and angiotensinogen

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Current and emerging drug targets in heart failure treatment

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