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  • Title: Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.
    Author: Ratni H, Rogers-Evans M, Bissantz C, Grundschober C, Moreau JL, Schuler F, Fischer H, Alvarez Sanchez R, Schnider P.
    Journal: J Med Chem; 2015 Mar 12; 58(5):2275-89. PubMed ID: 25654260.
    Abstract:
    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.
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