Identification and optimisation of novel sulfonamide, selective vasopressin V1B receptor antagonists

The synthesis and preliminary structure–activity relationships (SAR) of a novel class of vasopressin V 1B receptor antagonists are described. Hit compound 5 , identified via high throughput screening of the corporate collection, showed good activity in a V 1B binding assay ( K i 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A ‘deletion approach’ on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V 1B antagonist 9f ( K i 190 nM), with improved druglike characteristics.