Nahtlose Integration von Dosis-Wirkungs-basiertem Screening und Flusschemie: effiziente Erzeugung von Struktur-Aktivitäts-Beziehungen von β-Sekretase(BACE1)-Hemmern†
Corresponding Author
Dr. Michael Werner
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)Search for more papers by this authorChristoph Kuratli
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorCorresponding Author
Dr. Rainer E. Martin
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)Search for more papers by this authorDr. Remo Hochstrasser
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDavid Wechsler
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDr. Thilo Enderle
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDr. Alexander I. Alanine
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorProf. Dr. Horst Vogel
Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne (EPFL), Station 6, 1015 Lausanne (Schweiz)
Search for more papers by this authorCorresponding Author
Dr. Michael Werner
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)Search for more papers by this authorChristoph Kuratli
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorCorresponding Author
Dr. Rainer E. Martin
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)Search for more papers by this authorDr. Remo Hochstrasser
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDavid Wechsler
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDr. Thilo Enderle
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorDr. Alexander I. Alanine
Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Schweiz)
Search for more papers by this authorProf. Dr. Horst Vogel
Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne (EPFL), Station 6, 1015 Lausanne (Schweiz)
Search for more papers by this authorWir danken Dr. Hans Hilpert für hilfreiche Diskussionen, Roland Humm für das Bereitstellen der Bausteine A und B, Daniel Zimmerli, Roger Werder und Tom Kissling für technische Unterstützung sowie Dr. Annie Moisan und Prof. Klaus Müller für das Korrekturlesen des Manuskripts.
Abstract
Die Arzneistoffentwicklung stellt ein vielfältiges Aufgabenfeld dar, welches als grundlegendes Element die Erzeugung von Struktur-Aktivitäts-Beziehungen (SAR) durch wiederholte chemische Synthese und biologische Aktivitätsbestimmung maßgeschneiderter Moleküle beinhaltet. Hier berichten wir über die Entwicklung eines Fluss-basierten biochemischen Assays und seine nahtlose Einbindung in ein vollautomatisiertes System, bestehend aus flusschemischer Synthese, Aufreinigung und Quantifizierung in serieller Abfolge. Diese neuartige Synthese-Screening-Platform ermöglicht es, SAR-Daten von β-Sekretase-Hemmern in einer bisher unerreichten Durchlaufzeit von 1 Stunde anstelle mehrerer Tage zu erhalten. Die vollständige Automatisierung und Einbindung industrielle Prozesse hat seit jeher zu Produktivitätssteigerung und Kosteneinsparungen geführt. Diese Studie zeigt, wie diese Konzepte angewandt auf die Erzeugung von SAR-Daten, zu einem effizienteren Arzneistoffentwicklungsprozess führen können.
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