Direct Renin Inhibitors as a New Therapy for Hypertension

Webb, Randy L.; Schiering, Nikolaus; Sedrani, Richard; Maibaum, Jürgen

doi:10.1021/jm901885s

Cited by 68 publications

(53 citation statements)

References 208 publications

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“…1 Almost one-third of the U.S. adult population has high blood pressure (BP), which increases the risk of cardiovascular and renal disease and shortened life expectancy. 2−4 Various antihypertensive drugs have been developed, including diuretics, beta blockers, calcium channel blockers (CCBs), renin inhibitors, 5 angiotensinconverting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). 6,7 However, these drugs either lack sufficient efficacy or are associated with significant adverse effects.…”

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confidence: 99%

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

Barawkar¹,

Meru²,

Bandyopadhyay³

et al. 2011

ACS Med. Chem. Lett.

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L-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetatetreated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension. KEYWORDS: Hao2, hypertension, pyrazolecarboxylic acid, DOCA rat H uman hypertension is a complex, multifactorial disorder resulting from the interplay of multiple environmental and genetic factors, and this common disorder can lead to an increased risk of heart attack, stroke, and renal failure. The mechanisms underlying the initiation and maintenance of the hypertensive process remain unclear. 1 Almost one-third of the U.S. adult population has high blood pressure (BP), which increases the risk of cardiovascular and renal disease and shortened life expectancy. 2−4 Various antihypertensive drugs have been developed, including diuretics, beta blockers, calcium channel blockers (CCBs), renin inhibitors, 5 angiotensinconverting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). 6,7 However, these drugs either lack sufficient efficacy or are associated with significant adverse effects. In a search for a novel antihypertensive target, we have identified L-2-hydroxy acid oxidase (Hao2) 8 as a potential target for pharmacological intervention.L-2-Hydroxy acid oxidases are flavin mononucleotide (FMN)-dependent peroxisomal enzymes, which are members of the flavoenzyme family that are responsible for the oxidation of a number of L-2-hydroxy acids to ketoacids at the expense of molecular oxygen, resulting in the formation of hydrogen peroxide. Several examples of such enzymes have been identified in different organisms, e.g., glycolate oxidase from plants, lactate oxidase from Mycobacterium (L-lactate 2-monooxygenase), flavocytochrome b 2 from yeasts (L-lactate cytochrome c oxidoreductase), and mandelate dehydrogenase from Pseudomonas putida. 9 In mammals, this family of enzymes was first identified as an L-amino acid oxidase in the kidney and the liver of rats and later found to have activity similar to that of L-2-hydroxy acid. 10,11 Two α-hydroxy acid oxidases were also reported from hog renal cortex, named long chain L-α-hydroxy acid oxidase (Hao2) and short chain L-α-hydroxy acid oxidase (Hao1), because of their substrate specificity toward long and short carbon chain L-α-hydroxy acids, respectively. In both prokaryotes and eukaryotes, all the memb...

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confidence: 99%

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

Barawkar¹,

Meru²,

Bandyopadhyay³

et al. 2011

ACS Med. Chem. Lett.

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“…), were designed. The literature on existing and experimental DRIs is reviewed by Webb et al [170] and in other reviews [170][171][172][173][174][175][176]. …”

Section: Direct Renin Inhibitorsmentioning

confidence: 99%

Antihypertensive Drugs

Vardanyan

Hruby

2016

Synthesis of Best-Seller Drugs

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“…Specific inhibition of the aspartyl protease renin 4,5 which catalyzes the first and rate limiting step of the RAAS by cleaving angiotensinogen to angiotensin-1 may offer a beneficial therapeutic profile [6][7][8][9] as compared to previously marketed RAAS hypertension therapies. 10 This notion has triggered vast efforts at a number of pharmaceutical companies to identify low molecular weight direct renin inhibitors (DRI) 11,12 suitable for clinical development. Aliskiren 13,14 (1, Tekturna/Rasilez Ò , Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Significant affinity to CYP3A4 and hERG had been observed previously for multiple classes of new basic transition state DRI and appeared to be a persisting challenge in the development of nonpeptidic renin inhibitors. 11 We reasoned that reducing the overall lipophilicity by the incorporation of a more polar spacer group could potentially overcome the CYP3A4, hERG and high metabolic clearance issues without significantly impeding the permeability potential. A set of diverse amides and carbamates was therefore prepared ( Table 2).…”

Section: Introductionmentioning

confidence: 99%