Strategies To Reduce hERG K⁺ Channel Blockade. Exploring Heteroaromaticity and Rigidity in Novel Pyridine Analogues of Dofetilide

Abstract

Drug-induced blockade of the human ether-a-go-go-related gene K(+) channel (hERG) represents one of the major antitarget concerns in pharmaceutical industry. SAR studies of this ion channel have shed light on the structural requirements for hERG interaction but most importantly may reveal drug design principles to reduce hERG affinity. In the present study, a novel library of neutral and positively charged heteroaromatic derivatives of the class III antiarrhythmic agent dofetilide was synthesized and assessed for hERG affinity in radioligand binding and manual patch clamp assays. Structural modifications of the pyridine moiety, side chain, and peripheral aromatic moieties were evaluated, thereby revealing approaches for reducing hERG binding affinity. In particular, we found that the extra rigidity imposed close to the positively charged pyridine moiety can be very efficient in decreasing hERG affinity.

Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators

“…Therefore, it can be concluded that the binding site in the receptor imposes tight dimensional requirements for the size of the peptide linker and additional flexibility in the linker may lead to pronounce intra-cavitary blockade. Similar conclusions were reached in in-silico designs of minimally structured hERG1 blockers, as well as re-designed analogs of high-affinity blocker dofetilide [26], [27].…”

“…Several recent studies emphasized importance of drug rigidity for efficient binding to channel with a reduced blockade [26], [27]. We investigated the effect of the peptide-like chain linker between benzene rings.…”

Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of Kv11.1 Blockers

“…Compounds 19,20,24,25,[27][28][29][30][39][40][41][42][43][44][45][46] were newly synthesized in order to obtain compounds with various RT values besides a diverse range of K i and k on values. All other compounds were selected from our in-house library based on their distinct affinities and kinetic parameters, and synthesis of these compounds has been reported in our previously published studies.…”

“…The first series of compounds (S23a− e) were derived from commercially available 2,6-dibromopyridine and 1-alkynes with various lengths via a Sonogashira coupling reaction. 25 The final compounds (24, 25, and 27−29) were synthesized in relatively high yields by reduction of triple bonds to single bonds and methylation of neutral pyridines. 30 was obtained directly from S23e by methylation of the central nitrogen with a good yield of 94%.…”

“…36 Furthermore, introduction of different groups at the second benzene rings lowered their K v 11.1 affinities compared to the nonsubstituted compound (39−45 versus 38), indicating a possible steric hindrance of these groups in ligand binding. 22,25 Although the k on values showed a comparable decline to affinities because of the increased rigidity by an alkyne moiety (35 versus 38−46) and reduction of the aromatic rings (36 versus 37), the negative relationship between K i and k on values was not conspicuous for this series of compounds. For instance, compound 38 showed a smaller K i value as well as slower association rate than 39.…”