2. Academic Validation
  3. 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

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. 2016 Jan 19;11(2):199-206. doi: 10.1002/cmdc.201500269.
Franz von Nussbaum 1,  Volkhart M Li 2,  Daniel Meibom 3,  Sonja Anlauf 4,  Martin Bechem 5,  Martina Delbeck 5,  Michael Gerisch 6,  Axel Harrenga 7,  Dagmar Karthaus 4,  Dieter Lang 6,  Klemens Lustig 6,  Joachim Mittendorf 4,  Martina Schäfer 7,  Stefan Schäfer 5,  Jens Schamberger 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353, Berlin, Germany. franz.nussbaum@bayer.com.
  • 2 Lead Discovery Wuppertal, Bayer HealthCare AG, 42096, Wuppertal, Germany. volkhart.li@bayer.com.
  • 3 Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096, Wuppertal, Germany. daniel.meibom@bayer.com.
  • 4 Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096, Wuppertal, Germany.
  • 5 Department of Cardiology Research Wuppertal, Bayer HealthCare AG, 42096, Wuppertal, Germany.
  • 6 DMPK Wuppertal, Bayer HealthCare AG, 42096, Wuppertal, Germany.
  • 7 Lead Discovery, Structural Biology Berlin, Bayer HealthCare AG, 13353, Berlin, Germany.
PMID: 26333652 DOI: 10.1002/cmdc.201500269
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.

Keywords

Biginelli reaction; biological activity; elastase inhibitors; medicinal chemistry; pyrimidinones.

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