5A8X

Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor

Summary for 5A8X

• Entry DOI: 10.2210/pdb5a8x/pdb
• Related: 5A8Y 5A8Z
• Descriptor: Neutrophil elastase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: trypsin family fold, protease, hydrolase, hydrolase- inhibitor complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 24728.32

Authors

vonNussbaum, F.,Li, V.M.,Meibom, D.,Anlauf, S.,Bechem, M.,Delbeck, M.,Gerisch, M.,Harrenga, A.,Karthaus, D.,Lang, D.,Lustig, K.,Mittendorf, J.,Schaefer, M.,Schaefer, S.,Schamberger, J. (deposition date: 2015-07-17, release date: 2016-08-03, Last modification date: 2020-07-29)

Primary citation

von Nussbaum, F.,Li, V.M.,Meibom, D.,Anlauf, S.,Bechem, M.,Delbeck, M.,Gerisch, M.,Harrenga, A.,Karthaus, D.,Lang, D.,Lustig, K.,Mittendorf, J.,Schafer, M.,Schafer, S.,Schamberger, J.
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.
ChemMedChem, 11:199-206, 2016

PubMed 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.

PubMed: 26333652
DOI: 10.1002/cmdc.201500269

Experimental method

X-RAY DIFFRACTION (2.23 Å)