Design, synthesis, and biological evaluation of arylmethylpiperidines as Kv1.5 potassium channel inhibitors

Figures & data

Figure 1. (A) Structure of one Kv1.5 α-subunit with six membrane-spanning domains and the intracytoplasmic accessory β-subunits. (B) α and accessory β-subunits co-assemble as tetramers to form the functional channel.

Figure 2. Structures of (A) AVE-0118. (B) MK-0448. (C) S-0100176. (D) Amiodarone hydrochloride. (E) Vernakalant hydrochloride.

Figure 3. Structure of DDO-02001 and strategy for optimisation.

Scheme 1. Synthesis of DDO-02001 and DDO-02002. Reagents and conditions: (i) EDCI, DMAP, THF, r.t.; (ii) CF₃COOH, DMF, r.t.; (iii) K₂CO₃, CH₃CN, 80 °C, reflux.

Scheme 2. Synthesis of DDO-02003-DDO-02009. Reagents and conditions: (i) piperidin-4-one-hydrochloride, K₂CO_3, r.t.; (ii) NaB(OAc)₃H, anhydrous. ClCH₂CH₂Cl, r.t.

Table 1. Inhibition activities of DDO-02002-DDO-02009 on Kv1.5 channel

Comp.	L	R	hKv1.5 IC50 (μM)
DDO-02002	–CONH–	4-OCH3	8.96 ± 1.15
DDO-02003	–NH–	4-OCH3	1.57 ± 0.26
DDO-02004	–NH–CH2–	H	0.95 ± 0.13
DDO-02005	–NH–CH2–	4-OCH3	0.72 ± 0.08
DDO-02006	–NH–CH2–	4-F	3.24 ± 0.29
DDO-02007	–NH–CH2–	2-OCH3	>20
DDO-02008	–NH–CH2–	4-CH3	>20
DDO-02009	–NH–CH2–CH2–	H	>20
DDO-02001			17.71 ± 2.93

Figure 4. Effect of compound DDO-02005 and dronedarone on (A) atrial fibrillation, (B) atrial ERP and (C) ventricle ERP. Values of *p < 0.05, **p < 0.01 and ***p < 0.001 were considered statistically significant.

Figure 5. DDO-02005 inhibits the arrhythmia induced by aconitine in rats.

Table 2. Pharmacokinetic parameters regarding lead compound DDO-02005 (mean ± SD, n = 6)

Parameter	i.v.	p.o.
Dose (mg/kg)	1.00	1.25
t1/2 (h)	3.23 ± 1.07	6.25 ± 2.40
Cmax (μg/L)	90.23 ± 28.83	1.27 ± 0.40
AUC(0-t) (μg/L*h)	178.42 ± 39.33	4.41 ± 0.69
CL (L/h/kg)	5.83 ± 1.44	36.51 ± 2.54

Figure 6. Cardiovascular parameters of guinea pigs after treated with compound DDO-02005 (red) and Azimilide (blue), (A) QT interval. (B) QT_c interval. (C) QT_d interval. (D) QT_cd interval. (E) heart rate (HR). The values shown are the mean ± SD (n = 6).