Synthesis and Structure-Activity Relationship Studies of Diphenyl Ether Derivatives as BKCa Channel Openers

Abstract

The large-conductance Ca²⁺-activated K⁺ channel (BKCa channel) is highly expressed in the smooth muscle of the urinary bladder and mediates muscle relaxation. Therefore, BKCa channel activators are expected to address pathological symptoms associated with the overactivity of bladder smooth muscle. Our research team screened 8,364 compounds from the Korea Chemical Bank (KCB)’s GPCR-targeted library, leading to the discovery of a novel BKCa channel opener (LDD-4856) with superior activity compared to previously reported BKCa channel activators. Based on this previous research, compound 9c was synthesized; it exhibited better activity than LDD-4856. Additionally, key pharmacophores were validated, and an acid moiety was introduced to propose a new potent interaction. In this paper, the structure-activity relationships (SAR) and synthetic procedures of 19 diphenyl ether derivatives are discussed.