Display omitted •Novel V1b antagonists.•Markedly improved selectivity and pharmacokinetic profiles.•Improved half-life and brain penetration (rat PK).•In vivo efficacy at 3 mg/kg (ip, rat forced swim test).•High volume of distribution to mitigate high in vivo plasma clearance. Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3 mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.