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 library has been screened against ∼270 different targets and 15 phenotypic assays, and hits have been developed to form the basis of patents and spin-off companies. Here, we review the outcome of screening campaigns of the ELF, including the performance and physicochemical properties of the library, identification of possible frequent hitter compounds, and the effectiveness of the compound-sharing model.

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. This generates structural diversity and combines molecules with complementary physicochemical properties. In 2019, the screening library was updated to enable another 5 years of running innovative drug discovery projects. Here, we investigate the physicochemical and diversity properties of the updated compound collection. We show that it is highly diverse, drug-like, and complementary to commercial screening libraries.

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. 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.

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. However, despite intensive drug discovery efforts, even five decades later, no neutrophil elastase inhibitors are available for a disease-modifying treatment of (cardio)pulmonary diseases such as chronic obstructive pulmonary disease. Here, we critically review the attempts to develop effective human neutrophil elastase inhibitors while strongly focussing on recent developments. On purpose and with perspective distortion we focus on recent developments. One aim of this review is to classify the known HNE inhibitors into several generations, according to their binding modes. In general, there seem to be three major challenges in the development of suitable elastase inhibitors: (1) assuring sufficient potency, (2) securing selectivity, and (3) achieving metabolic stability especially under pathophysiological conditions. Impressive achievements have been made since 2001 with the identification of potent nonreactive, reversible small molecule inhibitors. The most modern inhibitors bind HNE via an induced fit with a frozen bioactive conformation that leads to a significant boost in potency, selectivity, and stability ('pre-adaptive pharmacophores'). These 5th generation inhibitors might succeed in re-establishing the protease-antiprotease balance in patients for the first time.

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). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.