Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier (IKur) current in human cells, has a crucial role in atrial fibrillation. Therefore, the design of selective Kv1.5 modulators is essential for the treatment of pathophysiological conditions involving Kv1.5 activity. This review summarizes the progress of molecular structures and the functionality of different types of Kv1.5 modulators, with a focus on clinical cardiovascular drugs and a number of active natural products, through a summarization of 96 compounds currently widely used. Furthermore, we also discuss the contributions of Kv1.5 and the regulation of the structure-activity relationship (SAR) of synthetic Kv1.5 inhibitors in human pathophysiology. SAR analysis is regarded as a useful strategy in structural elucidation, as it relates to the characteristics that improve compounds targeting Kv1.5. Herein, we present previous studies regarding the structural, pharmacological, and SAR information of the Kv1.5 modulator, through which we can assist in identifying and designing potent and specific Kv1.5 inhibitors in the treatment of diseases involving Kv1.5 activity.


Introduction
The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier (I Kur ) current in cells [1], is an attractive familial atrial fibrillation (AF) type 7 drug target, because it is selectively expressed in the atria but not in the ventricles of human cells [2]. AF is the most common cardiac arrhythmia facing physicians, afflicting 13% of men and 11% of women over 85 years of age. In atrial tissue from AF donors, the inhibition of I Kur extends the repolarization phase of the atrial cardiac action potential, thereby providing desirable antiarrhythmic effects without the risk of drug-induced 2 risk of drug-induced torsade de pointes. It is noteworthy that loss-of-function Kv1.5 mutations are associated with AF, and many companies are currently exploring IKur modulators for the treatment of AF [3].
The Kv1.5 protein is encoded by the KCNA5 gene with a length of 602 amino acids in mice (Unitprot Entry: Q61762) and rat (Unitprot Entry: P19024) sequences and 613 amino acids in the human sequence (Unitprot Entry: P22460). According to the Basic Local Alignment Search Tool (BLAST) result, the sequence of Kv1.5 is similar to homology targets Kv1.1, Kv1.2, and Kv1.3 in most regions, whereas differences mainly occur toward the start and end terminals of the sequence (see Figure 1C,D). The Kv1.5 channel belongs to the shaker-type voltage-gated K + channel family, and it comprises four pore-forming α-subunits, each containing six transmembrane segments, named S1-S6 [4,5]. A pore region is formed between the pore helix and S6 domain of each subunit, which contains the selectivity filter through which K + ions flow across the plasma membrane [6,7]. Currently, the structure of the Kv1.5 protein is still awaiting identification; however, alanine-scanning mutagenesis and homologous modeling studies provide us with some amino acids, including Thr479, Ile502, Val505, Ile508, and Val512, which reside within the deep pore (Thr479-Val481) and lower S6 (Cys500-Val512) regions as putative binding sites for open-channel blockers [8][9][10][11][12][13] (Figure 1B). This not only helps us to understand the drug targets more comprehensively, but also saves time with regard to the development of potential clinical candidates in the future. From this perspective, we highlight recent advances in the discovery of small molecules as modulators of Kv1.5, and we discuss the structure-activity relationship (SAR) studies of currently used synthetic Kv1.5 inhibitors.
Although the structure of Kv1.5 protein has not been characterized yet, current researches provide information for the development of Kv1.5 inhibitors according to fragment-based drug design and structure-based drug design. In regard to the design of Kv1.5 inhibitor, for the instance of the typical candidate vernakalant, in the pharmacophore model, hydrogen bond receptor, hydrogen bond donor, and hydrophobic groups should be present in the structure (Figure 2A) to play a role in the transmembrane effect to interact with the Kv1.5 channel. From the potential binding domain of vernakalant in Kv1.5 [8,14] (Figure 2B), we can see that the positively charged moiety bound in the cationophilic inner pore (mainly formed by electron-donating residues including alanine, leucine, and valine) formed a cationic "blocking particle" causing a block of the potassium channel; additionally, the uncharged dimethoxyphenyl moiety of a vernakalant has a tendency to bind in hydrophobic subunit interfaces including residues Ile 502 and Val 505. Functionally important residue isoleucine I502 in the inner helix S6 is exposed into the subunit interface of the pore module rather than into the inner pore. It is worth noting that mutations of Ile 502 decrease the potency of vernakalant, flecainide, and AVE0118, which are the ligands with a long hydrophobic tail in the side chain of the structure.
It seems that the introduction of heterocyclic rings including pyrrole (vernakalant, bepridil, clemizole, and BMS-394136) and piperdine (lobeline, CD-160130, bupivacaine, paroxetine, and donepezil) is important because these moieties usually influence the acidification conditions of the molecules, in which a potentially protonated and thus positively charged drug may enter deeply into the channel pore in a voltage-dependent way [15].

Synthetic Kv1.5 Inhibitors and SAR Investigations
In this section we collated information about chemical synthesis, pharmacological properties, and SAR investigations in the published literature from 2003 to 2019 and summarized them in a timeline. The previous work was briefly introduced in the description ofthe potential synthetic derivatives and chemical structure of compounds, and the SAR studies are listed in the corresponding figures in the perspective of medicinal chemistry. As we can see, multiple scaffolds include 5-methoxypsoralen (60,68), tetrahydroindolone (62)(63)(64)(65), benzopyran sulfonamides (70)(71)(72), dihydropyrazolopyrimidine (73,81), and phenylquinazoline (90)(91)(92). Compounds (86)(87)(88) have been reported to be effective in inhibiting Kv1.5, suggesting potential future directions for investigations about Kv1.5 inhibitors. It is noteworthy that research from Bristol-Myers Squibb has contributed greatly with data about pharmacology and pharmacokinetics of active compounds in blocking Kv1.5, increasing the possibility that we can conquer the diseases targeting Kv1.5. Inhibiting hKv1.5 current after long-term treatment, abbreviating the prolongation of action potential duration in chronic atrial fibrillation (AF). [31] 3 Vernakalant 794466-  Approved, investigation al
[32] 794466-  Approved, investigational HEK cells  Inhibiting hKv1.5 current with concentration-dependent acceleration of the apparent channel inactivation in both outside-out and inside-out patches.

13
Biomolecules 2020, 10   Blocking Kv1.5 current in an expression system and concentration-dependently elevated the plateau phase of atrial action potentials (APs). [59] 1272353-82-8 Phase 1 discontinued Mammalian L-929 cells Blocking hKv1.5 current with IC 50 value of 0.05 µM with an acceptable in vitroselectivity and liability profile and a good pharmacokinetic profile across species. [58]
[59] 875562-  Phase 1 discontinued HK2BN9 cells Blocking Kv1.5 current in an expression system and concentration-dependently elevated the plateau phase of atrial action potentials (APs). [59] Prolongating action potential duration (APD) and suppressed APs at high stimulation rates in sinus rhythm (SR) and paroxysmal AF (pAF) tissue.   In 2003, Peukert and co-workers [80] synthesized a series of ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel. Among the derivatives, the most potent compounds 57 (IC 50 : 0.7 µM) and 58 (IC 50 : 0.16 µM) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed three fold selectivity over Kv1.3 and no significant effect on the hERG channel and sodium currents (Figure 3).
Biomolecules 2020, 10, 10 19 of 34 In 2006, Blass et al. [83] synthesized a cluster of (2-phenethyl-2H-1,2,3-triazol-4-yl) (phenyl) methanone and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation. The results showed that O substitution in the 4-position of the acetophenone-derived portion of the scaffold is highly favored, and the most active compound 61 blockaded Kv1.5 for 99% at a concentration of 1 μM (Figure 6).   Subsequently, Wu et al. [85] designed and synthesized tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers. Compounds 64 and 65 showed good selectivity for the blockade of Kv1.5 (IC50: 0.13 μM for two compounds), moreover, in an anesthetized pig model, compounds 64 and 65 increased atrial ERP by about 28% and 18%, respectively, in the right atrium without affecting ventricular ERP (Figure 8). Based on a diisopropyl amide scaffold, a series of potent Kv1.5 ion channel antagonists were synthesized by Nanda and colleagues [86]. The most active derivative 66, which was a single active enantiomer of the diastereomerically pure racemic analog, exhibited significant atrial-selective effects in an in vivo model (IC50: 150 nM) (Figure 9). In 2006, Blass et al. [83] synthesized a cluster of (2-phenethyl-2H-1,2,3-triazol-4-yl) (phenyl) methanone and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation. The results showed that O substitution in the 4-position of the acetophenone-derived portion of the scaffold is highly favored, and the most active compound 61 blockaded Kv1.5 for 99% at a concentration of 1 μM (Figure 6).   Subsequently, Wu et al. [85] designed and synthesized tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers. Compounds 64 and 65 showed good selectivity for the blockade of Kv1.5 (IC50: 0.13 μM for two compounds), moreover, in an anesthetized pig model, compounds 64 and 65 increased atrial ERP by about 28% and 18%, respectively, in the right atrium without affecting ventricular ERP (Figure 8). Based on a diisopropyl amide scaffold, a series of potent Kv1.5 ion channel antagonists were synthesized by Nanda and colleagues [86]. The most active derivative 66, which was a single active enantiomer of the diastereomerically pure racemic analog, exhibited significant atrial-selective effects in an in vivo model (IC50: 150 nM) (Figure 9). Subsequently, Wu et al. [85] designed and synthesized tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers. Compounds 64 and 65 showed good selectivity for the blockade of Kv1.5 (IC 50 : 0.13 µM for two compounds), moreover, in an anesthetized pig model, compounds 64 and 65 increased atrial ERP by about 28% and 18%, respectively, in the right atrium without affecting ventricular ERP (Figure 8).
Biomolecules 2020, 10, 10 19 of 34 In 2006, Blass et al. [83] synthesized a cluster of (2-phenethyl-2H-1,2,3-triazol-4-yl) (phenyl) methanone and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation. The results showed that O substitution in the 4-position of the acetophenone-derived portion of the scaffold is highly favored, and the most active compound 61 blockaded Kv1.5 for 99% at a concentration of 1 μM (Figure 6).   Subsequently, Wu et al. [85] designed and synthesized tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers. Compounds 64 and 65 showed good selectivity for the blockade of Kv1.5 (IC50: 0.13 μM for two compounds), moreover, in an anesthetized pig model, compounds 64 and 65 increased atrial ERP by about 28% and 18%, respectively, in the right atrium without affecting ventricular ERP (Figure 8). Based on a diisopropyl amide scaffold, a series of potent Kv1.5 ion channel antagonists were synthesized by Nanda and colleagues [86]. The most active derivative 66, which was a single active enantiomer of the diastereomerically pure racemic analog, exhibited significant atrial-selective effects in an in vivo model (IC50: 150 nM) (Figure 9). Based on a diisopropyl amide scaffold, a series of potent Kv1.5 ion channel antagonists were synthesized by Nanda and colleagues [86]. The most active derivative 66, which was a single active enantiomer of the diastereomerically pure racemic analog, exhibited significant atrial-selective effects in an in vivo model (IC 50 : 150 nM) (Figure 9). Trotter and co-workers [87] designed and synthesized a group of isoquinoline-3-nitriles as orally Kv1.5 antagonists for the treatment of AF. The ethanolamide derivative 67 exhibited improved potency (Kv1.5 HT-Clamp IC50: 60 nM), excellent selectivity versus hERG, and good pharmacokinetic properties. Rat EP experiments confirmed that the compound potently increased ARP without significant effects on AVRP − (Figure 10).  Jackson and co-workers [89] prepared several classes of thiazolidine-based Kv1.5 blockers. The most promising analogue 69 derived from 3,4-dimethylacetophenone exhibited the strongest inhibitory effect with an IC50 value of 69 nM (Figure 12). Trotter and co-workers [87] designed and synthesized a group of isoquinoline-3-nitriles as orally Kv1.5 antagonists for the treatment of AF. The ethanolamide derivative 67 exhibited improved potency (Kv1.5 HT-Clamp IC50: 60 nM), excellent selectivity versus hERG, and good pharmacokinetic properties. Rat EP experiments confirmed that the compound potently increased ARP without significant effects on AVRP − (Figure 10).  Jackson and co-workers [89] prepared several classes of thiazolidine-based Kv1.5 blockers. The most promising analogue 69 derived from 3,4-dimethylacetophenone exhibited the strongest inhibitory effect with an IC50 value of 69 nM (Figure 12). In 2007, Eun et al. [88] synthesized multiple psoralen derivatives as hKvl.5 channel blockers. Among them, compound 68 was the most potent in blocking hKv1.5 (IC 50 : 27.4 nM), much stronger than the lead compound psoralen. Compound 68 accelerated the inactivation kinetics of the hKvl.5 channel and slowed the deactivation kinetics of the hKv1.5 current resulting in a tail crossover phenomenon. Compound 68 inhibited the hKvl.5 current in a use-dependent manner ( Figure 11). Trotter and co-workers [87] designed and synthesized a group of isoquinoline-3-nitriles as orally Kv1.5 antagonists for the treatment of AF. The ethanolamide derivative 67 exhibited improved potency (Kv1.5 HT-Clamp IC50: 60 nM), excellent selectivity versus hERG, and good pharmacokinetic properties. Rat EP experiments confirmed that the compound potently increased ARP without significant effects on AVRP − (Figure 10).  Jackson and co-workers [89] prepared several classes of thiazolidine-based Kv1.5 blockers. The most promising analogue 69 derived from 3,4-dimethylacetophenone exhibited the strongest inhibitory effect with an IC50 value of 69 nM (Figure 12). Jackson and co-workers [89] prepared several classes of thiazolidine-based Kv1.5 blockers. The most promising analogue 69 derived from 3,4-dimethylacetophenone exhibited the strongest inhibitory effect with an IC 50 value of 69 nM (Figure 12).   Vaccaro and co-workers [90] synthesized a series of dihydropyrazolopyrimidine analogues as Kv1.5 inhibitors. The most promising compound 73 showed the best potential in suppressing Kv1.5, with inhibitory effects on hERG (69%) and INa 10 (42%) at a concentration of 10 μM (Figure 15). Lloyd et al. [90] synthesized a series of benzopyran sulfonamides and determined Kv1.5 potassium channel blocking effects. Among the productions, derivative 70 exhibited the most significant activity (IC50: 57 nM), and a moderate inhibition (35%) of hERG at a concentration of 10 μM (Figure 13).  Vaccaro and co-workers [90] synthesized a series of dihydropyrazolopyrimidine analogues as Kv1.5 inhibitors. The most promising compound 73 showed the best potential in suppressing Kv1.5, with inhibitory effects on hERG (69%) and INa 10 (42%) at a concentration of 10 μM (Figure 15). Lloyd et al. [90] synthesized a series of benzopyran sulfonamides and determined Kv1.5 potassium channel blocking effects. Among the productions, derivative 70 exhibited the most significant activity (IC50: 57 nM), and a moderate inhibition (35%) of hERG at a concentration of 10 μM (Figure 13).  Vaccaro and co-workers [90] synthesized a series of dihydropyrazolopyrimidine analogues as Kv1.5 inhibitors. The most promising compound 73 showed the best potential in suppressing Kv1.5, with inhibitory effects on hERG (69%) and INa 10 (42%) at a concentration of 10 μM (Figure 15). Vaccaro and co-workers [90] synthesized a series of dihydropyrazolopyrimidine analogues as Kv1.5 inhibitors. The most promising compound 73 showed the best potential in suppressing Kv1.5, with inhibitory effects on hERG (69%) and I Na 10 (42%) at a concentration of 10 µM (Figure 15). Biomolecules 2020, 10, 10 22 of 34 Figure 15. Dihydropyrazolopyrimidine derivatives.
In 2008, Gross and co-workers [92] synthesized aryl sulfonamido tetralin as a Kv1.5 inhibitor according to the basis of previous work. Among the productions, compound 74 exhibited remarkable Kv1.5 inhibitions with an IC50 value of 90 nM; in addition, moderate hERG inhibition was detected at the dose of 10 μM (39%), indicating the potential for further development of clinical candidates ( Figure 16).  In 2010, Lloyd and co-workers [58] developed a series of pyrazolodihydropyrimidines as potent and selective Kv1.5 blockers based on previous studies. The most promising analogue BMS-394136 (76) displayed excellent activity in blocking Kv1.5 (IC50: 50 nM) and very good selectivity over hERG, sodium, and L-type calcium ion channels with good pharmacokinetic parameters ( Figure 18).   In 2010, Lloyd and co-workers [58] developed a series of pyrazolodihydropyrimidines as potent and selective Kv1.5 blockers based on previous studies. The most promising analogue BMS-394136 (76) displayed excellent activity in blocking Kv1.5 (IC50: 50 nM) and very good selectivity over hERG, sodium, and L-type calcium ion channels with good pharmacokinetic parameters ( Figure 18). According to the structure of marketed drugs amiodarone and vernakalant, Blass et al. [93] synthesized a series of imidazolidinone derivatives as a potential treatment for atrial arrhythmia. KVI-020/WYE-160020 (75) exhibited the efficacy in clinically relevant models of AF and mechanistic models of the cardiac action potential with acceptable pharmacokinetic and pharmaceutical properties. In 2008, Gross and co-workers [92] synthesized aryl sulfonamido tetralin as a Kv1.5 inhibitor according to the basis of previous work. Among the productions, compound 74 exhibited remarkable Kv1.5 inhibitions with an IC50 value of 90 nM; in addition, moderate hERG inhibition was detected at the dose of 10 μM (39%), indicating the potential for further development of clinical candidates ( Figure 16).  In 2010, Lloyd and co-workers [58] developed a series of pyrazolodihydropyrimidines as potent and selective Kv1.5 blockers based on previous studies. The most promising analogue BMS-394136 (76) displayed excellent activity in blocking Kv1.5 (IC50: 50 nM) and very good selectivity over hERG, sodium, and L-type calcium ion channels with good pharmacokinetic parameters ( Figure 18). In 2012, Blass [94] prepared several heteroarylsulfonamides as Kv1.5 inhibitors. The active analogues 77, 78 and 79 exhibited 100% inhibition of Kv1.5 using stably transfected HEK293 cells and the FLIPR potassium ion channel assay, suggesting good potential for further investigation ( Figure  19). Finlay and colleagues [95] prepared several dihydropyrazolo[1,5-a]pyrimidine derivatives. Among the synthetic compounds, compound 80 showed potential to be a selective IKur inhibitor with Kv1.5 IC50 of 0.15 μM and hERG with an IC50 value >10 μM. Furthermore, favorable pharmacokinetic properties in rats and dogs of 80 were determined; compound 80 was identified with less than 1% GSH adducts formation with an improved PK profile and equivalent PD efficacy to the lead compound ( Figure 20). In 2013, triazolo and imidazo were introduced into the active scaffold dihydropyrazolopyrimidine [96]. Trifluoromethylcyclohexyl triazole analogue 81 was identified as a potent and selective Kv1.5 inhibitor (IC50: 133 nM) with an acceptable PK and liability profile. Compound 81 demonstrated an improved rat PK profile and was advanced to the rat PD model ( Figure 21). In 2012, Blass [94] prepared several heteroarylsulfonamides as Kv1.5 inhibitors. The active analogues 77, 78 and 79 exhibited 100% inhibition of Kv1.5 using stably transfected HEK293 cells and the FLIPR potassium ion channel assay, suggesting good potential for further investigation (Figure 19). In 2012, Blass [94] prepared several heteroarylsulfonamides as Kv1.5 inhibitors. The active analogues 77, 78 and 79 exhibited 100% inhibition of Kv1.5 using stably transfected HEK293 cells and the FLIPR potassium ion channel assay, suggesting good potential for further investigation ( Figure  19). Finlay and colleagues [95] prepared several dihydropyrazolo[1,5-a]pyrimidine derivatives. Among the synthetic compounds, compound 80 showed potential to be a selective IKur inhibitor with Kv1.5 IC50 of 0.15 μM and hERG with an IC50 value >10 μM. Furthermore, favorable pharmacokinetic properties in rats and dogs of 80 were determined; compound 80 was identified with less than 1% GSH adducts formation with an improved PK profile and equivalent PD efficacy to the lead compound ( Figure 20). In 2013, triazolo and imidazo were introduced into the active scaffold dihydropyrazolopyrimidine [96]. Trifluoromethylcyclohexyl triazole analogue 81 was identified as a potent and selective Kv1.5 inhibitor (IC50: 133 nM) with an acceptable PK and liability profile. Compound 81 demonstrated an improved rat PK profile and was advanced to the rat PD model ( Figure 21). Finlay and colleagues [95] prepared several dihydropyrazolo[1,5-a]pyrimidine derivatives. Among the synthetic compounds, compound 80 showed potential to be a selective I Kur inhibitor with Kv1.5 IC 50 of 0.15 µM and hERG with an IC 50 value >10 µM. Furthermore, favorable pharmacokinetic properties in rats and dogs of 80 were determined; compound 80 was identified with less than 1% GSH adducts formation with an improved PK profile and equivalent PD efficacy to the lead compound ( Figure 20). In 2012, Blass [94] prepared several heteroarylsulfonamides as Kv1.5 inhibitors. The active analogues 77, 78 and 79 exhibited 100% inhibition of Kv1.5 using stably transfected HEK293 cells and the FLIPR potassium ion channel assay, suggesting good potential for further investigation ( Figure  19). Finlay and colleagues [95] prepared several dihydropyrazolo[1,5-a]pyrimidine derivatives. Among the synthetic compounds, compound 80 showed potential to be a selective IKur inhibitor with Kv1.5 IC50 of 0.15 μM and hERG with an IC50 value >10 μM. Furthermore, favorable pharmacokinetic properties in rats and dogs of 80 were determined; compound 80 was identified with less than 1% GSH adducts formation with an improved PK profile and equivalent PD efficacy to the lead compound ( Figure 20). In 2013, triazolo and imidazo were introduced into the active scaffold dihydropyrazolopyrimidine [96]. Trifluoromethylcyclohexyl triazole analogue 81 was identified as a potent and selective Kv1.5 inhibitor (IC50: 133 nM) with an acceptable PK and liability profile. Compound 81 demonstrated an improved rat PK profile and was advanced to the rat PD model ( Figure 21). In 2013, triazolo and imidazo were introduced into the active scaffold dihydropyrazolopyrimidine [96]. Trifluoromethylcyclohexyl triazole analogue 81 was identified as a potent and selective Kv1.5 inhibitor (IC 50 : 133 nM) with an acceptable PK and liability profile. Compound 81 demonstrated an improved rat PK profile and was advanced to the rat PD model ( Figure 21).  Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC50 of 0.08 μM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23). However, both hERG and IKs active and remarkable safety in rats of compound 83 was detected and judged unsuitable for in vivo testing; conversely, the derivative 84 was regarded as a hopeful compound for further development with Kv1.5 IC50, IKs, Ceu20, and QTmax change values for 1.0 μM, >33%, 0.6 μM, and <10%, respectively. In 2014, the subsequent study was updated [99], and a series of lactam sulfonamide derivatives was prepared and the Kv1.5 inhibitory potency was evaluated. The most promising candidate 85 inhibited Kv1.5 with an IC50 value of 0.21 μM and caused a marked increase in the atrium ERP with a Ceu20 of 0.35 μM, which was at the same order of magnitude as the IC50 value from the human cellular assay. The human hERG channel was blocked by compound 85 with an IC50 value of 30 μM, indicating a 140 fold margin of the hERG and Kv1.5 in vitro values. No measurable change was noted in the QTinterval in the rabbit experiments, which also indicated a good margin to block of the hERG channel. The compound 85 was well tolerated in rabbits with no signs of the CNS-like side effects observed for other Kv1.5 blockers (Figure 24).  Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC50 of 0.08 μM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23). However, both hERG and IKs active and remarkable safety in rats of compound 83 was detected and judged unsuitable for in vivo testing; conversely, the derivative 84 was regarded as a hopeful compound for further development with Kv1.5 IC50, IKs, Ceu20, and QTmax change values for 1.0 μM, >33%, 0.6 μM, and <10%, respectively. In 2014, the subsequent study was updated [99], and a series of lactam sulfonamide derivatives was prepared and the Kv1.5 inhibitory potency was evaluated. The most promising candidate 85 inhibited Kv1.5 with an IC50 value of 0.21 μM and caused a marked increase in the atrium ERP with a Ceu20 of 0.35 μM, which was at the same order of magnitude as the IC50 value from the human cellular assay. The human hERG channel was blocked by compound 85 with an IC50 value of 30 μM, indicating a 140 fold margin of the hERG and Kv1.5 in vitro values. No measurable change was noted in the QTinterval in the rabbit experiments, which also indicated a good margin to block of the hERG channel. The compound 85 was well tolerated in rabbits with no signs of the CNS-like side effects observed for other Kv1.5 blockers (Figure 24). Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC 50 of 0.08 µM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23). However, both hERG and IKs active and remarkable safety in rats of compound 83 was detected and judged unsuitable for in vivo testing; conversely, the derivative 84 was regarded as a hopeful compound for further development with Kv1.5 IC 50 , IKs, C eu20 , and QT max change values for 1.0 µM, >33%, 0.6 µM, and <10%, respectively.  Olsson and co-workers [98] possessed design and pharmacological evaluation of multiple potential hits targeting on Kv1.5. The compound 83 performed the best in vitro activity with Kv1.5 IC50 of 0.08 μM in diphenylphosphinic amide and diphenylphosphine oxide analogues ( Figure 23). However, both hERG and IKs active and remarkable safety in rats of compound 83 was detected and judged unsuitable for in vivo testing; conversely, the derivative 84 was regarded as a hopeful compound for further development with Kv1.5 IC50, IKs, Ceu20, and QTmax change values for 1.0 μM, >33%, 0.6 μM, and <10%, respectively. In 2014, the subsequent study was updated [99], and a series of lactam sulfonamide derivatives was prepared and the Kv1.5 inhibitory potency was evaluated. The most promising candidate 85 inhibited Kv1.5 with an IC50 value of 0.21 μM and caused a marked increase in the atrium ERP with a Ceu20 of 0.35 μM, which was at the same order of magnitude as the IC50 value from the human cellular assay. The human hERG channel was blocked by compound 85 with an IC50 value of 30 μM, indicating a 140 fold margin of the hERG and Kv1.5 in vitro values. No measurable change was noted in the QTinterval in the rabbit experiments, which also indicated a good margin to block of the hERG channel. The compound 85 was well tolerated in rabbits with no signs of the CNS-like side effects observed for other Kv1.5 blockers (Figure 24). In 2014, the subsequent study was updated [99], and a series of lactam sulfonamide derivatives was prepared and the Kv1.5 inhibitory potency was evaluated. The most promising candidate 85 inhibited Kv1.5 with an IC 50 value of 0.21 µM and caused a marked increase in the atrium ERP with a C eu20 of 0.35 µM, which was at the same order of magnitude as the IC 50 value from the human cellular assay. The human hERG channel was blocked by compound 85 with an IC 50               Johnson et al. [100] synthesized phenethylaminoheterocycles and assayed for inhibition of the Kv1.5 potassium ion channel as a potential approach to the treatment of atrial fibrillation. Combination of the indazole with a cyclohexane-based template gave the most promising derivative 86 (Kv1.5 IC50: 138 nM) which demonstrated significant prolongation of AERP in the rabbit pharmacodynamic model (Figure 25).    Finlay and co-workers [103] explored phenylquinazoline derivatives as Kv1.5 inhibitors. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (90) was identified as a potent and ion channel selective inhibitor (Kv1.5 IC 50 : 90 nM, hERG inhibition: 43% at 10 µM) with robust efficacy in the pre-clinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model ( Figure 28).
best derivative with pharmacological parameters including Kv1.5, Ikur, and Ikr(hERG) IC50 values for 29, 11 and 1.28 × 10 5 nM, respectively, and pharmacokinetic parameters including dog in vivo atrial refractory period EC10 for 14 nM and threshold change in ventricular refractory period >25 μM. Configuration of chiral carbon is important, R-isomer is far better than S-isomer Non-substitution on the skeleton is good for activity, this area is the main metabolite position 3,5-diCl is better than 3-CF 3 and 3-Cl, pyridine ring is better than benzene ring 94 Figure 31. SAR of oroidin MK-1832.

Conclusion
Herein the target and the pharmacological properties with structural, pharmacological, and SAR information of Kv1.5 modulators were discussed. Detailed descriptions of pharmacology parameters In 2019, Kajanus and colleagues [106] prepared potassium channel blocking 1,2-bis(aryl)ethane-1, 2-diamines active as antiarrhythmic agents. The most promising analogue 95 displayed significant nanomolar potency in blocking Kv1.5 in human atrial myocytes (IC 50 : 1.7 µM, I Kur IC 50 : 60 nM) and based on the PD data, the estimated dose for men was 700 mg/day ( Figure 32). Configuration of chiral carbon is important, R-isomer is far better than S-isomer Non-substitution on the skeleton is good for activity, this area is the main metabolite position 3,5-diCl is better than 3-CF 3 and 3-Cl, pyridine ring is better than benzene ring 94 Figure 31. SAR of oroidin MK-1832.

Conclusion
Herein the target and the pharmacological properties with structural, pharmacological, and SAR information of Kv1.5 modulators were discussed. Detailed descriptions of pharmacology parameters Recently, natural products with novel structural motif as a Kv1.5 inhibitor also gained progress in this field. In the sequence of the isolation of compound debromoaplysiatoxin A (38) and debromoaplysiatoxin B (39) [63], Tang and co-workers [14] identified other novel aplysiatoxin derivatives from the marine cyanobacterium Lyngbya sp. Among them, compound oscillatoxin E (96) with the hexane-tetrahydropyran of a spirobicyclic system skeleton exhibited the strongest Kv1.5 inhibition (IC 50 : 0.79 µM) in the CHO cells at an HP of -80 mV (Figure 33). Configuration of chiral carbon is important, R-isomer is far better than S-isomer Non-substitution on the skeleton is good for activity, this area is the main metabolite position 3,5-diCl is better than 3-CF 3 and 3-Cl, pyridine ring is better than benzene ring 94 Figure 31. SAR of oroidin MK-1832.

Conclusion
Herein the target and the pharmacological properties with structural, pharmacological, and SAR information of Kv1.5 modulators were discussed. Detailed descriptions of pharmacology parameters

Conclusions
Herein the target and the pharmacological properties with structural, pharmacological, and SAR information of Kv1.5 modulators were discussed. Detailed descriptions of pharmacology parameters and SAR studies provide an actionable path forward for medicinal chemists to optimize the structure of Kv1.5 modulators. Further experiments should improve the PK and safety after the effectiveness is proven. Design and development of potential and selective Kv1.5 modulators are important and challenging tasks. Based on the existing pharmacophoric requirements and potential protein structure parsed in the future, some novel effective Kv1.5 modulators may be designed and prepared [107,108]. However, gaps exist in the scientific studies on Kv1.5 modulators. Firstly, the selectivity of existing Kv1.5 modulators remains to be investigated, and more specific modulators aiming at the Kv1.5 channel are needed in the future. Secondly, from the point of application, the market of AF is relatively small, and the sales condition of marked anti-AF agents is not satisfactory as a whole, thus more in-depth pharmacological investigation of roles of Kv1.5 are required in the future. Moreover, the definite structure of Kv1.5 protein is still vacant, difficulties and potential fallacy are still consistent in the design of modulators only estimating by the pocket of homologous models.
SAR investigation is crucial for the development of novel promising clinical candidates. It is anticipated that the information compiled in this review article not only updates researchers with the recently reported pharmacology and SAR of Kv1.5 modulators, but also motivates them to design and synthesize promising Kv1.5 modulators with improved medicinal properties.

Conflicts of Interest:
The authors declare no conflict of interest.