Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach

From a micromolar high throughput
screening hit 7,
the successful complementary application of a chemogenomic approach
and of a scaffold hopping exercise rapidly led to a low single digit
nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable
tool compounds which demonstrated a V1a mediated central in
vivo effect. This novel series was further optimized through
parallel synthesis with a focus on balancing lipophilicity to achieve
robust aqueous solubility while avoiding P-gp mediated efflux. These
efforts led to the discovery of the highly potent and selective brain-penetrant
hV1a antagonist RO5028442 (8) suitable for human clinical
studies in people with autism.