title: Discovery of 1H-pyrazolo[3,4-b]pyridines as potent dual orexin receptor antagonists (DORAs).
abstract: Compound rac-1 was identified by high throughput screening. Here we report SAR studies and MedChem optimization towards the highly potent dual orexin receptor antagonists (S)-2 and (S)-3. Furthermore, strategies to overcome the suboptimal physicochemical properties are highlighted and the pharmacokinetic profiles of representative compounds is presented.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland. Electronic address: dirk.behnke@novartis.com.
authors.forename: Dirk
authors.initials: D
authors.lastname: Behnke
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Cotesta
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gee
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland; The Florey Institute of Neuroscience and Mental Health, Parkville Campus, Kenneth Myer Building at Genetics Lane, on Royal Parade, University of Melbourne, Parkville, 3010, Australia.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Grit
authors.initials: G
authors.lastname: Laue
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
authors.forename: Arndt
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Medicinal Chemistry, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560100, India.
authors.forename: Sangamesh
authors.initials: S
authors.lastname: Badiger
authors.affiliation: Medicinal Chemistry, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560100, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Chaudhari
authors.affiliation: Medicinal Chemistry, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560100, India.
authors.forename: Murali
authors.initials: M
authors.lastname: Chebrolu
authors.affiliation: Medicinal Chemistry, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560100, India.
authors.forename: Chetan
authors.initials: C
authors.lastname: Pandit
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland; School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville Campus, Kenneth Myer Building at Genetics Lane, on Royal Parade, University of Melbourne, Parkville, 3010, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D051379:Mice; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000068796:Orexin Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; C000611190:rac-1 compound
keywords: Antagonists; GPCRs; Insomnia; Orexin