Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis.

Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation.

The dual role of thiourea in the thiotrifluoromethylation of alkenes.

Alkenes substituted with a thiourea undergo C-CF followed by intramolecular C-S bond formation with the Togni reagent and trifluoroacetic acid (TFA) at room temperature; thiols and thioamides are not suitable S-sources for this reaction. This anti-addition process involves a CF radical, and affords CF-substituted thiazolines and thiazines for medicinal applications. A metal or photoredox catalyst is not required as the thiourea acts as a reductant, as well as serving as an S-source capable of adding to a C-centered radical.

ChEMBLSpace--a graphical explorer of the chemogenomic space covered by the ChEMBL database.

The ChEMBLSpace graphical explorer enables the identification of compounds from the ChEMBL database, which exhibit a desirable polypharmacology profile. This profile can be predefined or created iteratively, and the tool can be extended to other data sources.

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.

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.