N-[3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl]-heteroaromatic carboxamide as selective α_1A/1D-adrenoceptor...

Dual α_1A/1D-adrenergic receptor (AR) antagonists are a mainstay treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Building on the phenylpiperazine pharmacophore of naftopidil, our previous work identified the linker region as a critical structural determinant for subtype selectivity. However, we recognized that the secondary hydroxyl group within the previously employed linker (e.g., in lead R-17) could represent a potential metabolic liability. In this study, we strategically optimized the linker moiety to achieve a precise balance between subtype selectivity and metabolic stability. We designed and synthesized nineteen novel propane-linked derivatives by eliminating the hydroxyl group and introducing diverse aromatic carboxamide moieties. Among them, compound 15 featuring a 5-benzo[d][1,3]dioxole group emerged as a highly potent α_1A/1D antagonist. Structure-activity relationship (SAR) and molecular docking confirmed that the streamlined propane linker retains the optimal chain length to prevent the key salt bridge interaction with D^3.32 in the α_1B subtype, thereby preserving the structural basis for high selectivity. Crucially, our head-to-head evaluation in rat liver microsomes validated our design hypothesis: the removal of the hydroxyl group dramatically improved metabolic stability, extending the half-life (T_1/2) from 6.1 min (R-17) to 31.5 min (15). This work establishes compound 15 as a promising lead candidate that successfully integrates the selectivity-determining linker scaffold with enhanced drug-like properties.