Cardiovascular response to small-molecule APJ activation

Ason, Brandon; Chen, Yinhong; Guo, Qi; Hoagland, Kimberly M.; Chui, Ray W.; Fielden, Mark R.; Sutherland, Weston; Chen, Rhonda; Zhang, Ying; Mihardja, Shirley; Ma, Xiaochuan; Li, Xun; Sun, Yaping; Liu, Dongming; Nguyen, Khanh Q.; Jing-hong, Wang; Li, Ning; Rajamani, Sridharan; Qu, Yusheng; Gao, BaoXi; Boden, Andrea M.; Chintalgattu, Vishnu; Turk, J. R.; Chan, Janice; Hu, Liaoyuan A.; Dransfield, Paul J.; Houze, Jonathan B.; Wong, Jing Man; Ma, Ji; Pattaropong, Vatee; Véniant, Murielle M.; Vargas, Hugo M.; Swaminath, Gayathri; Khakoo, Aarif Y.

doi:10.1172/jci.insight.132898

Cited by 34 publications

(31 citation statements)

References 79 publications

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“…IV administration of the G αi -biased agonist CMF-019 increases cardiac contractility in rats [108]. The characteristics of the oral small-molecule apelin agonist AMG986 [109] and of the first antibody agonist against the AR to be developed [110] have recently been published.…”

Section: Development Of Novel Drugsmentioning

confidence: 99%

The emerging role of the apelinergic system in kidney physiology and disease

Janssens

Decuypere

Bammens

et al. 2021

Nephrology Dialysis Transplantation

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The apelinergic system (AS) is a novel pleiotropic system with an essential role in renal and cardiovascular physiology and disease, including water homeostasis and blood pressure regulation. It consists of two highly conserved peptide ligands, apelin and apela, and a G-protein-coupled apelin receptor. The two ligands have many isoforms and a short half-life, and exert both similar and divergent effects. Vasopressin, apelin and their receptors colocalize in hypothalamic regions essential for body fluid homeostasis and interact at the central and renal levels to regulate water homeostasis and diuresis in inverse directions. In addition, the AS and renin angiotensin system interact both systemically and in the kidney, with implications for the cardiovascular system. A role for the AS in diverse pathological states, including disorders of sodium and water balance, hypertension, heart failure, pre-eclampsia, acute kidney injury, sepsis and diabetic nephropathy has recently been reported. Furthermore, several metabolically stable apelin analogs have been developed, with potential applications in diverse diseases. We review here what is currently known about the physiological functions of the AS, focusing on renal, cardiovascular and metabolic homeostasis, and the role of the AS in associated diseases. We also describe several hurdles and research opportunities worthy of the attention of the nephrology community.

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Section: Development Of Novel Drugsmentioning

confidence: 99%

The emerging role of the apelinergic system in kidney physiology and disease

Janssens

Decuypere

Bammens

et al. 2021

Nephrology Dialysis Transplantation

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“…Administration of apelin or a small molecule apelinR agonist increases cardiac output in vivo in rodents (111,147). Administration of apelin or apelin analogs in rodents post-myocardial infarction improved functional recovery and reduced infarct size, most likely due to increase NO production and angiogenesis (110,(148)(149)(150). Administration of apelin for 2 weeks after aortic banding prevented cardiac remodeling by inhibiting myocyte hypertrophy, cardiac fibrosis and ventricular dysfunction (151).…”

Section: Cardiovascular Actions Of Apelinmentioning

confidence: 99%

“…Numerous approaches ( Table 1 ), such as PEGylation ( 107 – 109 , 112 , 113 ), synthetic modifications to the RPRL motif of apelin ( 18 ), palmitoylation and the use of unnatural amino acids ( 38 , 103 , 107 , 114 , 115 ), or main-chain modifications (cyclization) ( 106 , 116 , 117 ), have now been used to increase the half-life of apelin peptides. Recent studies have reported the development of nonpeptidic ApelinR agonists that mimic the signaling properties of apelin, some of them are orally active ( Table 1 ) ( 104 , 110 , 111 ).…”

Section: The Apelin/avp Balance and Hyponatremiamentioning

confidence: 99%

Apelin and Vasopressin: The Yin and Yang of Water Balance

et al. 2021

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Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect via its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring via the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin in vivo. In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (s.c.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.

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“…38 As such the apelin receptor (APJ), a widely expressed G protein-coupled receptor found in the heart and thought to be important for cardiovascular function and heart development, presents an intriguing and promising novel target for the direct treatment of this grievous illness. 39 During the course of the discovery and development of the novel APJ agonist AMG 986, we identified a series of biologically active compounds derived from sulfonamide moieties bearing well-defined patterns of vicinal stereocenters. 40 In addition to the syn-1,2-dimethyl motif ultimately found in AMG 986, the team discovered clinically relevant analogs that contained syn-and anti-stereopatterns with ether substitution replacing one of the methyl groups (Figure 6).…”

Section: Asymmetric Reduction Strategies: Novel Apelin Receptor Agonimentioning

confidence: 99%

Building Complexity and Achieving Selectivity through Catalysis – Case Studies from the Pharmaceutical Pipeline

Beaver

Caille

Farrell

et al. 2020

Synlett

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The last decade of small-molecule process development has witnessed a trend of increasing molecular complexity for clinical candidates. The continued advance of novel catalytic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with increasing complexity. This Account highlights several examples from the process chemistry laboratories at Amgen.1 Introduction2 The Evolution of Molecular Complexity3 Catalysis as a Lever to Build Complexity4 Ru(II)-Catalyzed Dynamic Kinetic Resolution Enabling the Manufacture of AMG 2325 Application of Enzymatic Desymmetrization toward Scale-Up of the MCL-1 Inhibitor AMG 1766 Synthesis of Fucostatin 1: Catalytic Asymmetric Transfer Hydrogenation7 Manganese-Catalyzed Asymmetric Epoxidation To Prepare a Carfilzomib Intermediate8 Asymmetric Reduction Strategies: Novel Apelin Receptor Agonists and AMG 9869 Conclusions

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Cardiovascular response to small-molecule APJ activation

Cited by 34 publications

References 79 publications

The emerging role of the apelinergic system in kidney physiology and disease

The emerging role of the apelinergic system in kidney physiology and disease

Apelin and Vasopressin: The Yin and Yang of Water Balance

Building Complexity and Achieving Selectivity through Catalysis – Case Studies from the Pharmaceutical Pipeline

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