Discovery of 1H-pyrazolo[3,4-b]pyridines as potent dual orexin receptor antagonists (DORAs)

Dirk Behnke; Simona Cotesta; Samuel Hintermann; Markus Fendt; Christine E Gee; Laura H Jacobson; Grit Laue; Arndt Meyer; Trixie Wagner; Sangamesh Badiger; Vinod Chaudhari; Murali Chebrolu; Chetan Pandit; Daniel Hoyer; Claudia Betschart

doi:10.1016/j.bmcl.2015.10.055

Discovery of 1H-pyrazolo[3,4-b]pyridines as potent dual orexin receptor antagonists (DORAs)

Bioorg Med Chem Lett. 2015 Dec 1;25(23):5555-60. doi: 10.1016/j.bmcl.2015.10.055. Epub 2015 Oct 19.

Authors

Affiliations

¹ Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland. Electronic address: dirk.behnke@novartis.com.
² Global Discovery Chemistry, Novartis Institutes for BioMedical Research, WKL-136.3.26, CH-4002 Basel, Switzerland.
³ Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
⁴ 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.
⁵ Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
⁶ Medicinal Chemistry, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II, Electronic City, Hosur Road, Bangalore 560100, India.
⁷ 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.

PMID: 26522950
DOI: 10.1016/j.bmcl.2015.10.055

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.

Keywords: Antagonists; GPCRs; Insomnia; Orexin.

MeSH terms

Administration, Intravenous
Administration, Oral
Animals
Crystallography, X-Ray
Drug Discovery*
Mice
Molecular Structure
Orexin Receptor Antagonists / chemical synthesis
Orexin Receptor Antagonists / chemistry*
Orexin Receptor Antagonists / pharmacology*
Protein Binding / drug effects
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology*

Substances

Orexin Receptor Antagonists
Pyrazoles
Pyridines
rac-1 compound