Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY‐8040 in a Pulmonary Arterial Hypertension Rat Model

Nussbaum, Franz von; Li, Volkhart M.; Meibom, Daniel; Anlauf, Sonja; Bechem, Martin; Delbeck, Martina; Gerisch, Michael; Harrenga, Axel; Karthaus, Dagmar; Lang, Dieter; Lustig, Klemens; Mittendorf, Joachim; Schäfer, Martina; Schäfer, Stefan; Schamberger, Jens

doi:10.1002/cmdc.201500269

Cited by 29 publications

(20 citation statements)

References 27 publications

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“…In the few published reports, it could be shown that specific proteins expressed by neutrophils, such as myeloperoxidase (MPO) and neutrophil elastase (NE), are elevated in peripheral plasma from PH patients and correlated with the severity of PAH and clinical outcome [ 130 ]. Selective NE inhibitors attenuated or even reversed PAH and pulmonary vascular remodeling in the rat model of monocrotaline-induced PAH, and they are the focus of current clinical investigation [ 131 , 132 ]. Even more exciting from a clinical perspective, late intervention with an MPO inhibitor stopped the progression of experimental chronic obstructive pulmonary disease and partially protected against PAH [ 132 ].…”

Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

142

109

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Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

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Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

142

109

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“…AZD9668 and BAY 85-8501 are in clinical trials (Phase II) for the treatment of patients with CF, COPD, bronchiectasis and pulmonary disease 18 , 76 , 80 . BAY-8040 showed excellent potency, selectivity, and improved the cardiac function in a rat model 81 .…”

Section: Exogenous and Therapeutic Neutrophil Serine Protease Inhibitmentioning

confidence: 94%

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Bronze-da-Rocha¹,

Santos-Silva²

2018

Int. J. Biol. Sci.

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End-stage renal disease (ESRD), the last stage of chronic kidney disease (CKD), is characterized by chronic inflammation and oxidative stress. Neutrophils are the front line cells that mediate an inflammatory response against microorganisms as they can migrate, produce reactive oxygen species (ROS), secrete neutrophil serine proteases (NSPs), and release neutrophil extracellular traps (NETs). Serine proteases inhibitors regulate the activity of serine proteases and reduce neutrophil accumulation at inflammatory sites. This review intends to relate the role of neutrophil elastase in CKD and the effects of neutrophil elastase inhibitors in predicting or preventing inflammation.

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“…The proteolytic activity of serine proteases, which is essential for the maintenance of important host functions, can also be harmful if not properly regulated, and a number of regulatory mechanisms are present (Von Nussbaum et al, ). For example, these proteases are stored as inactive precursors in specialized compartments, such as azurophil granules for serine proteases.…”

Section: Introductionmentioning

confidence: 99%

Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

Giovannoni

Cantini

Crocetti

et al. 2019

Drug Development Research

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Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme.HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC 50 = 15-51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad. K E Y W O R D S human neutrophil elastase inhibitors, molecular docking, pyrrolo[2,3-b]pyridine

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Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY‐8040 in a Pulmonary Arterial Hypertension Rat Model

Cited by 29 publications

References 27 publications

Perivascular Inflammation in Pulmonary Arterial Hypertension

Perivascular Inflammation in Pulmonary Arterial Hypertension

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Further modifications of 1H‐pyrrolo[2,3‐b]pyridine derivatives as inhibitors of human neutrophil elastase

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