Synthesis and structure–activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor

•11 new phenylpiperazines derived from LASSBio 772 has been designed and synthesized.•Affinities for human α1-AR subtypes in radioligand binding assays were assessed.•Antagonist profiles at α1-AR subtypes in functional bioassays were evaluated.•Among the newly synthesized compounds, potent ligands were identified.•SAR-analysis identified new hits for further search for improved α1-AR agents.

Arylpiperazines 2–11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide