Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.

Abstract

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.

• Authors: Patrick Schnider, Caterina Bissantz, Andreas Bruns, Cosimo Dolente, Erwin Goetschi, Roland Jakob-Roetne, Basil Künnecke, Thomas Mueggler, Wolfgang Muster, Neil Parrott, Emmanuel Pinard, Hasane Ratni, Céline Risterucci, Mark Rogers-Evans, Markus von Kienlin, Christophe Grundschober
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 4 Pg. 1511-1525 (02 27 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 31951127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Pyridines
• Receptors, Vasopressin
• Triazoles
• Benzodiazepines
• balovaptan

Topics

• Adolescent
• Adult
• Animals
• Antidiuretic Hormone Receptor Antagonists (chemical synthesis, pharmacokinetics, therapeutic use)
• Autism Spectrum Disorder (drug therapy, metabolism)
• Benzodiazepines (chemical synthesis, pharmacokinetics, therapeutic use)
• Brain (metabolism)
• Child
• Clinical Trials as Topic
• Drug Discovery
• Female
• Humans
• Male
• Mammals
• Pyridines (chemical synthesis, pharmacokinetics, therapeutic use)
• Receptors, Vasopressin (metabolism)
• Triazoles (chemical synthesis, pharmacokinetics, therapeutic use)