APJ agonist / BMS - LARVOL DELTA

Screening apelin analogues and a small molecule agonist as effective cardiovascular therapeutics against reperfusion injury. (PubMed, RSC Med Chem) - "We further assessed two metabolically stable apelin peptide analogues previously developed in our lab and compared them to a small-molecule agonist, BMS-986224, for biased agonist properties. Using radioligand displacement assays and blood pressure assays, we found that the retro-inverso peptides lacked apelin receptor binding affinity and physiological activity...In contrast, CbzPEG6-NMeLeu17A2 not only provided cardioprotective effects but also significantly lowered blood pressure. These findings highlight the potential of NMeLeu13A2 for targeted therapeutics and underscore the promise of apelin-based analogues in addressing ischemic reperfusion injury."

Journal • Cardiovascular • Reperfusion Injury

Design and preparation of N-linked hydroxypyridine-based APJ agonists. (PubMed, Bioorg Med Chem Lett) - "We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists. (PubMed, ACS Med Chem Lett) - "Recently we disclosed clinical lead BMS-986224 (1), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr)apelin-13 in an acute rat pressure-volume loop model. 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."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Identification of 6-​Hydroxy-​5-​phenyl​sulfonylpyrimidin-​4(1H)​-​one APJ Receptor Agonists. (PubMed, Bioorg Med Chem Lett) - "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."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

APLN/APLNR Signaling Controls Key Pathological Parameters of Glioblastoma. (PubMed, Cancers (Basel)) - "Both APLN and the Apelin receptor (APLNR) are upregulated in GBM cells and control tumor cell invasiveness...In addition, we discuss how manipulation of APLN/APLNR signaling in GBM leads to the normalization of tumor vessels and thereby supports chemotherapy, reduces edema, and improves anti-tumorigenic immune reactions. Hence, therapeutic targeting of APLN/APLNR signaling offers an interesting option to address different pathological hallmarks of GBM."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure. (PubMed, Circ Heart Fail) - "We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure."

Journal • Preclinical • Anesthesia • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology