The European Lead Factory: Results from a decade of collaborative, public-private, drug discovery programs.

The European Lead Factory (ELF) is a consortium of universities and small and medium-sized enterprises (SMEs) dedicated to drug discovery, and the pharmaceutical industry. This unprecedented consortium provides high-throughput screening, triage, and hit validation, including to non-consortium members. The ELF library was created through a novel compound-sharing model between nine pharmaceutical companies and expanded through library synthesis by chemistry-specialized SMEs.

The European Lead Factory: An updated HTS compound library for innovative drug discovery.

Through the European Lead Factory model, industry-standard high-throughput screening and hit validation are made available to academia, small and medium-sized enterprises, charity organizations, patient foundations, and participating pharmaceutical companies. The compound collection used for screening is built from a unique diversity of sources. It brings together compounds from companies with different therapeutic area heritages and completely new compounds from library synthesis.

Donated chemical probes for open science.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible.

Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly.

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores.

Alpha-1 antitrypsin deficiency is linked with an increased risk of suffering from lung emphysema. This discovery from the 1960s led to the development of the protease-antiprotease (im)balance hypothesis: Overshooting protease concentrations, especially high levels of elastase were deemed to have an destructive effect on lung tissue. Consequently, it was postulated that efficient elastase inhibitors could alleviate the situation in patients.

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.

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.

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH).

Prediction of a potentially effective dose in humans for BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling.

Aims: The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans.

Methods: A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose.

Results: The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life.

Chromanol derivatives--a novel class of CETP inhibitors.

Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.

Novel tetrahydrochinoline derived CETP inhibitors.

In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.

Dibenzodioxocinones--a new class of CETP inhibitors.

Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma.