N-[3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl]-heteroaromatic carboxamide as selective α1A/1D-adrenoceptor antagonists: SAR study and metabolic stability evaluation.

Dual α1A/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 α1A/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 D3.32 in the α1B 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 (T1/2) 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.