5A8X: Crystal Structure Of Human Neutrophil Elastase In Complex With A Dihydropyrimidone Inhibitor

Citation:
Abstract
Human neutrophil elastase (HNE) is a key driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions. Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance. Accordingly, there has been an intensive search for potent and selective HNE inhibitors with suitable pharmacokinetics that would allowing oral administration in patients. Based on the chemical probe BAY-678 and the clinical candidate BAY 85-8501 we explored further ring topologies along the equator of the parent pyrimidinone lead series. Novel ring systems were annulated in the east, yielding imidazolo-, triazolo-, and tetrazolopyrimidines in order to ensure additional inhibitor-HNE contacts beyond the S1 and the S2 pocket of HNE. The western annulation of pyridazines led to the polar pyrimidopyridazine BAY-8040, which combines excellent potency and selectivity with a promising pharmacokinetic profile. In vivo efficacy with regard to decreasing cardiac remodeling and amelioration of cardiac function was shown in a monocrotaline-induced rat model for pulmonary arterial hypertension. This demonstrated in vivo proof of concept in animals.
PDB ID: 5A8XDownload
MMDB ID: 141469
PDB Deposition Date: 2015/7/17
Updated in MMDB: 2016/08
Experimental Method:
x-ray diffraction
Resolution: 2.23  Å
Source Organism:
Similar Structures:
Biological Unit for 5A8X: monomeric; determined by author and by software (PISA)
Molecular Components in 5A8X
Label Count Molecule
Protein (1 molecule)
1
Neutrophil Elastase(Gene symbol: ELANE)
Molecule annotation
Chemicals (6 molecules)
1
3
2
2
3
1
* Click molecule labels to explore molecular sequence information.

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