RESUMEN
The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.
Asunto(s)
Química Farmacéutica , Industria Farmacéutica , Ecosistema , Europa (Continente)RESUMEN
Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler-Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for compounds (±)-13, (±)-16, (-)-20 and (±)-28 are also reported.
Asunto(s)
Alcaloides de Amaryllidaceae/síntesis química , Magnoliopsida/química , Modelos Moleculares , Estructura MolecularRESUMEN
Pharmaceutical companies often refer to 'screening their library' when performing high-throughput screening (HTS) on a corporate compound collection to identify lead structures for small-molecule drug discovery programs. Characteristics of such a library, including the size, chemical space covered, and physicochemical properties, often determine the success of a screening campaign. Therefore, strategies to maintain and enhance the overall quality of screening collections are crucial to stay competitive and to cope with the 'novelty erosion' that is observed gradually. The Next Generation Library Initiative (NGLI), the enhancement of Bayer's HTS collection by 500000 newly designed compounds within 5 years, is addressing exactly this challenge. Here, we describe this collaborative project, which involves all internal medicinal chemists in a crowd-sourcing approach, as well as selected external partners, to reach this ambitious goal.
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Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Bibliotecas de Moléculas Pequeñas , Industria Farmacéutica , Control de CalidadRESUMEN
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/químicaAsunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , 3',5'-GMP Cíclico Fosfodiesterasas , GMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Disfunción Eréctil/tratamiento farmacológico , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Masculino , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/fisiología , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocycles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. The lack of isoform selectivity demonstrated with isoform-selective transient THR transfection assays has been confirmed by corresponding in vivo studies.
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Compuestos Heterocíclicos/farmacología , Imitación Molecular , Hormonas Tiroideas/farmacología , Relación Estructura-ActividadRESUMEN
Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
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3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Compuestos Heterocíclicos/farmacología , Concentración 50 Inhibidora , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Novel heterocycle-fused thyromimetics are presented carrying indoles or indazoles instead of the phenolic group in T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. Moderate THRbeta selectivity (approx. 10-fold) was observed in the indole series using isoform-selective transient THR transfection assays.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Imitación Molecular , Receptores de Hormona Tiroidea/agonistas , Animales , Sitios de Unión , Bioensayo , Compuestos Heterocíclicos/farmacología , Indazoles/química , Indoles/química , Ligandos , Fenoles/química , Relación Estructura-Actividad , Transfección , Triyodotironina/farmacologíaRESUMEN
2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.