Details

Autor(en) / Beteiligte

• von Nussbaum, Franz
• 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

Titel

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

Ist Teil von

• ChemMedChem, 2016-01, Vol.11 (2), p.199-206

Ort / Verlag

Germany: Blackwell Publishing Ltd

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. Exploring new rings! Human neutrophil elastase (HNE) is a driver of inflammation in pulmonary arterial hypertension (PAH). Herein we describe the discovery of BAY‐8040, a small‐molecule inhibitor with nanomolar potency and good pharmacokinetics. BAY‐8040 shows in vivo efficacy in a PAH rat model, thereby demonstrating proof of concept in animals.