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- | Journal: Targeting the apelin system for the treatment of cardiovascular diseases. (Pubmed Central) - Nov 13, 2023
Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.
- azelaprag (BGE-105) / BioAge Labs
Activation of the apelin receptor, implicated in a key aging pathway by analysis of longitudinal human data, ameliorates multiple mechanisms that drive neuroinflammation and neurodegeneration (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_8294;
Daily oral administration of BGE-105 for 7 days suppressed circulating levels of age-related proinflammatory cytokines, increased levels of BDNF in the hippocampus, and reversed age-induced BBB dysfunction, suggesting that BGE-105 restores the BBB through its anti-inflammatory effects in the periphery. Taken together, our results suggest that apelin receptor agonism with an orally available small molecule represents a novel approach for treating chronic age-related neuroinflammation and neurodegeneration, and for mitigating the effects of inflammation on the BBB.
- A First-in-Human Single/Multiple Ascending Dose Study of ANPA-0073, a Novel Small Molecule G-protein Biased Apelin Receptor Agonist, in Healthy Volunteers (Walter E. Washington Convention Center, Area B, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_6922;
CONCLUSIONS. ANPA-0073 is a small molecule G-protein biased APJ agonist with a good safety profile with potential to treat apelin-related cardiopulmonary diseases such as pulmonary arterial hypertension and idiopathic pulmonary fibrosis.
- | Journal: A Novel Peptide Elabela is Associated with Hypertension-Related Subclinical Atherosclerosis. (Pubmed Central) - Dec 1, 2022
ANPA-0073 is a small molecule G-protein biased APJ agonist with a good safety profile with potential to treat apelin-related cardiopulmonary diseases such as pulmonary arterial hypertension and idiopathic pulmonary fibrosis. This study demonstrated for the first time that circulating elabela declined in a higher stage of hypertension and hypertensive patients with increased carotid IMT, implicating that elabela may be involved in the pathogenesis of hypertension-associated subclinical atherosclerosis.
- | LY294002 / Eli Lilly
Preclinical, Journal: Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects. (Pubmed Central) - Oct 5, 2022
We further revealed that exogenous ELA-21-induced inhibition of proliferation and PI3K/Akt signaling were amplified by the PI3K/Akt inhibitor LY294002, while the APJ receptor antagonist F13A abolished ELA-21-induced PI3K/Akt inhibition and Nrf2 activation in VSMCs. In conclusion, we demonstrate that ELA-21 alleviates vascular remodeling through anti-inflammatory, anti-oxidative and anti-proliferative effects in SHRs, indicating that ELA-21 may be a therapeutic agent for treating hypertension.
- | Journal: Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor. (Pubmed Central) - Jun 4, 2022
This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified.
- || azelaprag (BGE-105) / BioAge Labs
P1 data, Journal: A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients. (Pubmed Central) - Apr 24, 2022
P1
Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule.
- || Review, Journal: Apelin Pathway in Cardiovascular, Kidney, and Metabolic Diseases: Therapeutic role of Apelin Analogs and Apelin Receptor Agonists. (Pubmed Central) - Mar 24, 2022
In this context, apelin analogs with enhanced proteolytic stability and synthetic ApelinR agonists emerged as promising pharmacological alternatives. In this review, we focus on discussing the putative roles of the apelin pathway in various physiological systems from function to dysfunction, and emphasizing the therapeutic potential of newly generated metabolically stable apelin analogs and non-peptide ApelinR agonists.
- Biphenyl Acid and Aryl Hydroxypyrimidinone Derivatives as APJ Receptor Agonists (Room 1B (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_2184;
The lead molecule in the biphenyl acid series compared favorably with the endogenous ligand (Pyr1) Apelin-13 in terms of in vitro potency, activation of APJ signaling pathways, and acute in vivo hemodynamic response in rodents. In parallel, SAR development of the aryl hydroxypyrimidinone series led to the identification of potent and orally bioavailable APJ agonists.
- | Journal: Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure. (Pubmed Central) - Jan 26, 2022
Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.
- | APJ agonist / BMS
Journal: Identification of 6-Hydroxy-5-phenylsulfonylpyrimidin-4(1H)-one APJ Receptor Agonists. (Pubmed Central) - Jan 11, 2022
In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.
- | APJ agonist / BMS
Journal: Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists. (Pubmed Central) - Nov 21, 2021
Herein we describe the structure-activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4(1H)-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1.
- [VIRTUAL] Identification of pyrimidinone amides as potent APJ receptor agonists for the potential treatment of heart failure (Room: Virtual Room) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_3964;
Further adjustment of polarity by modifying the N1 substituted aryl group and re-optimization for potency of the C5 position led to potent compounds with improved permeability which resulted in the identification of our backup candidate. This candidate displayed excellent pharmacokinetic (PK) profiles in rat, dog and cyno, demonstrated robust pharmacodynamic (PD) efficacy in rodent heart failure (HF) models and also showed an acceptable safety profile in preclinical toxicology studies.
- indomethacin / Generic mfg.
[VIRTUAL] GASTROPROTECTIVE ACTION OF APELIN/AJP SYSTEM AGAINST ISCHEMIA-REPERFUSION INJURY. ROLE OF OXIDATIVE STRESS, NITRIC OXIDE AND SENSORY NEUROPEPTIDES (Poster Exhibition) - Jul 20, 2021 - Abstract #UEGW2021UEGW_4172;
Rats were pretreated with L-NAME (5 mg/kg i.g.), 2) indomethacin (2 mg/kg i.g.), and 3) capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves.by qPCR... 1) apelin/APJ signaling inhibits gastric I/R damage by enhancing gastric microcirculation, down-regulating pro-inflammatory cytokines and biomarkers, and by inhibiting lipid peroxidation and I/R-induced oxidative stress, and 2) apelin-induced gastric protection is likely mediated by NO and sensory neuropeptides, but appears to be independent of the PG / COX biosynthetic pathway.
- indomethacin / Generic mfg.
[VIRTUAL] GASTROPROTECTIVE ACTION OF APELIN/AJP SYSTEM AGAINST ISCHEMIA-REPERFUSION INJURY. ROLE OF OXIDATIVE STRESS, NITRIC OXIDE AND SENSORY NEUROPEPTIDES (Poster Exhibition) - Jul 20, 2021 - Abstract #UEGW2021UEGW_1992;
Rats were pretreated with L-NAME (5 mg/kg i.g.), 2) indomethacin (2 mg/kg i.g.), and 3) capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves.by qPCR... 1) apelin/APJ signaling inhibits gastric I/R damage by enhancing gastric microcirculation, down-regulating pro-inflammatory cytokines and biomarkers, and by inhibiting lipid peroxidation and I/R-induced oxidative stress, and 2) apelin-induced gastric protection is likely mediated by NO and sensory neuropeptides, but appears to be independent of the PG / COX biosynthetic pathway.
- indomethacin / Generic mfg.
[VIRTUAL] GASTROPROTECTIVE ACTION OF APELIN/AJP SYSTEM AGAINST ISCHEMIA-REPERFUSION INJURY. ROLE OF OXIDATIVE STRESS, NITRIC OXIDE AND SENSORY NEUROPEPTIDES (Poster Exhibition) - Jul 20, 2021 - Abstract #UEGW2021UEGW_161;
Rats were pretreated with L-NAME (5 mg/kg i.g.), 2) indomethacin (2 mg/kg i.g.), and 3) capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves.by qPCR... 1) apelin/APJ signaling inhibits gastric I/R damage by enhancing gastric microcirculation, down-regulating pro-inflammatory cytokines and biomarkers, and by inhibiting lipid peroxidation and I/R-induced oxidative stress, and 2) apelin-induced gastric protection is likely mediated by NO and sensory neuropeptides, but appears to be independent of the PG / COX biosynthetic pathway.
- | Simdax (levosimendan IV) / AbbVie
Journal: Inotropic Assessment in Engineered 3D Cardiac Tissues using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in the Biowire II Platform. (Pubmed Central) - Jul 17, 2021
In addition, myosin and troponin activators increase contraction duration. These results indicate that ECTs generated in the Biowire II platform can identify inotropes with different mechanisms and provides a human-based in-vitro model for evaluating potential therapeutics.
- | Journal: Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BK Channels. (Pubmed Central) - Jun 16, 2021
The lack of inhibitory effect on BK channels makes it unlikely that activation of APJ receptors in coronary arteries would adversely affect coronary flow by creating a vasoconstrictive environment. It can be expected that apelin or other APJ receptor agonists in development will not interfere with the vasodilator effects of endogenous BK channel openers.
- || Clinical, Journal: Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate. (Pubmed Central) - Jun 5, 2021
This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.
- | Preclinical, Journal: Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice. (Pubmed Central) - Jun 5, 2021
Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.
- | Journal: Identification of potent pyrazole based APELIN receptor (APJ) agonists. (Pubmed Central) - Feb 7, 2021
Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.
- | Preclinical, Journal: The Role of Apelin/APJ in a Mouse Model of Oxygen-induced Retinopathy. (Pubmed Central) - Jan 2, 2021
Furthermore, the expression of p-mTOR, p-Akt, and p-Erk were all up-regulated in OIR mice whereas F13A suppressed them instead. Our results suggest that apelin/APJ signaling pathway is a key factor for hypoxia-induced pathologic angiogenesis, which is a very promising new target for the treatment of ROP.
- [VIRTUAL] APELIN-RECEPTOR AGONIST PROMOTES NEURONAL INSULIN SENSITIVITY—IMPLICATION OF THERAPEUTIC POTENTIAL OF ALZHEIMER’S DISEASE () - Dec 24, 2020 - Abstract #ADPD2021ADPD_1238;
CMF-019 enhances insulin sensitivity and inhibits GSK3bthrough PI3K/AKT activation. Orally active CMF-019 may implicate the thereuptic potential of CMF-019.
- | Preclinical, Journal: Systemic Administration of an Apelin Receptor Agonist Prevents NMDA-Induced Loss of Retinal Neuronal Cells in Mice. (Pubmed Central) - Dec 18, 2020
Furthermore, oral administration of ML233 protected against the decrease in the STR amplitudes and the loss of retinal ganglion cells caused by NMDA. These results suggest that systemic administration of ML233 protected retinal neurons from NMDA receptor-mediated excitotoxicity and that drugs activating the apelin receptor may be a new candidate for preventing the progression of these retinal diseases.
- Opsumit (macitentan) / Nippon Shinyaku, J&J
[VIRTUAL] G Protein Biased Peptide Apelin Receptor Agonist Reverses Sugen/hypoxia-induced Pulmonary Hypertension as Effectively as the Endothelin Antagonist, Macitentan (OnDemand) - Sep 22, 2020 - Abstract #AHA2020AHA_4511;
These results suggest that systemic administration of ML233 protected retinal neurons from NMDA receptor-mediated excitotoxicity and that drugs activating the apelin receptor may be a new candidate for preventing the progression of these retinal diseases. The results suggest chronic treatment with MM07 is beneficial in this animal model and support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.
- AMG 986 /
[VIRTUAL] Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Amg 986, A Novel Small Molecule Apelin Receptor Agonist, In Healthy Subjects And Heart Failure Patients (Poster Hall - ePosters) - Sep 10, 2020 - Abstract #HFSA2020HFSA_277;
The results suggest chronic treatment with MM07 is beneficial in this animal model and support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease. In healthy subjects and in HF patients, short-term treatment with AMG 986 was well tolerated.
- | Journal: Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury. (Pubmed Central) - Jul 29, 2020
Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.
- | Preclinical, Journal: A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension. (Pubmed Central) - Jul 18, 2020
Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.
- | Journal: Biphenyl Acid Derivatives as APJ Receptor Agonists. (Pubmed Central) - Jul 16, 2020
Compound 15a demonstrated comparable in vitro potency to apelin-13, the endogenous peptidic ligand for the APJ receptor. In vivo, compound 15a demonstrated a dose-dependent improvement in the cardiac output in male Sprague Dawley rats with no significant changes in either mean arterial blood pressure or heart rate, consistent with the hemodynamic profile of apelin-13 in an acute pressure volume loop model.
- | MK-2206 / Merck (MSD), quercetin (LY294002) / Eli Lilly
Preclinical, Journal: Exacerbated pressor and sympatho-excitatory effects of central Elabela in spontaneously hypertensive rats. (Pubmed Central) - May 13, 2020
Chronic PVN infusion of ELA-21 induced sympathetic activation, hypertension and AVP release accompanied with cardiovascular remodeling in normotensive WKY. In conclusion, ELA-21 in PVN induces exacerbated pressor and sympatho-excitatory effects in hypertensive rats via PI3K-Akt pathway.