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

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.