1,595
Views
0
CrossRef citations to date
0
Altmetric
Research Papers

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

, , , &
Pages 462-471 | Received 09 Sep 2021, Accepted 09 Dec 2021, Published online: 10 Jan 2022

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 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 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.

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 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, K2CO3, r.t.; (ii) NaB(OAc)3H, anhydrous. ClCH2CH2Cl, r.t.

Scheme 2. Synthesis of DDO-02003-DDO-02009. Reagents and conditions: (i) piperidin-4-one-hydrochloride, K2CO3, r.t.; (ii) NaB(OAc)3H, anhydrous. ClCH2CH2Cl, r.t.

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

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 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.

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)

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

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

Supplemental Material

Download PDF (644.8 KB)