RESUMEN
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.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Pulmonares/tratamiento farmacológico , Proteínas Inhibidoras de Proteinasas Secretoras/uso terapéutico , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Pulmonares/metabolismo , Proteínas Inhibidoras de Proteinasas Secretoras/química , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismoRESUMEN
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 â¼270 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.
Asunto(s)
Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Industria Farmacéutica , UniversidadesRESUMEN
Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.
Asunto(s)
Guanilato Ciclasa , Hipertensión , Humanos , Guanilil Ciclasa Soluble/metabolismo , Guanilato Ciclasa/metabolismo , Hipertensión/tratamiento farmacológico , Vasodilatadores , Piridinas/farmacología , Piridinas/uso terapéutico , Óxido Nítrico/metabolismoRESUMEN
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. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSION: The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hidroxiquinolinas/administración & dosificación , Modelos Biológicos , Animales , Biometría , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxiquinolinas/farmacocinética , Hidroxiquinolinas/farmacología , Masculino , Ratones , Ratones Transgénicos , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Benzopiranos/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Cromanos/química , Compuestos de Espiro/química , Administración Oral , Animales , Benzopiranos/síntesis química , Benzopiranos/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/metabolismo , Cromanos/síntesis química , Cromanos/farmacocinética , Perros , Humanos , Ratones , Ratones Transgénicos , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
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 5â¯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.
Asunto(s)
Descubrimiento de Drogas/métodos , Industria Farmacéutica/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Europa (Continente) , Humanos , Preparaciones Farmacéuticas/química , Bibliotecas de Moléculas PequeñasRESUMEN
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.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipolipemiantes/química , Quinolinas/química , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Perros , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/farmacocinética , Ratones , Ratones Transgénicos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/químicaRESUMEN
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. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (
Asunto(s)
Sondas Moleculares/metabolismo , Farmacología/métodos , Proteínas/metabolismo , Tecnología Farmacéutica/métodosRESUMEN
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. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Guanilil Ciclasa Soluble/metabolismo , Relación Estructura-Actividad , Administración Intravenosa , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Técnicas de Química Sintética , Perros , Hepatocitos/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Humanos , Masculino , NG-Nitroarginina Metil Éster/efectos adversos , Pirimidinas/administración & dosificación , Ratas Transgénicas , Ratas Wistar , Guanilil Ciclasa Soluble/genéticaRESUMEN
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.
Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Elastasa de Leucocito/antagonistas & inhibidores , Proteínas Inhibidoras de Proteinasas Secretoras/química , Proteínas Inhibidoras de Proteinasas Secretoras/farmacología , Piridazinas/química , Piridazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Hipertensión Pulmonar/metabolismo , Elastasa de Leucocito/metabolismo , Modelos Moleculares , Estructura Molecular , Proteínas Inhibidoras de Proteinasas Secretoras/síntesis química , Piridazinas/síntesis química , Pirimidinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Congelación , Elastasa de Leucocito/antagonistas & inhibidores , Enfermedades Pulmonares/enzimología , Proteínas Inhibidoras de Proteinasas Secretoras/farmacología , Pirimidinonas/farmacología , Sulfonas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Elastasa de Leucocito/metabolismo , Conformación Molecular , Proteínas Inhibidoras de Proteinasas Secretoras/química , Pirimidinonas/química , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
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. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.