Patent Application
20220054438
The present invention relates to a family of compounds which are capable of modulating KChIP2 proteins. Therefore, the invention could fall within the field of pharmacology.
KChIPs are accessory proteins which interact with voltage-dependent potassium channels (KV) and belong to the superfamily of neuronal calcium sensors. To date, four isoforms, KChIP1-4, have been described. They all contain a variable N-terminal domain and a C-terminal domain with four EF-hand Ca2+-binding domains. In KChIP1-3, the C-terminal region is highly conserved. These three isoforms share a common mechanism of action regarding the modification of the KV4 potassium channel: they increase the potassium current density, they slow down channel inactivation kinetics and speed up the recovery from inactivation. KV4.3 channels generate two currents, depending on the tissue in which they are expressed: a) Ito in the heart and b) A-type currents in the brain. In both cases, the recapitulation of the electrophysiological characteristics is only achieved when channels KV4.3 are expressed together with KChIP subunits. Current Ito is essential for the control of cardiac excitability and is primarily mediated by KV4.3+KChIP2 complexes, whereas ISA current participates in the control of neuronal transmission and is mediated by KV4.3+KChIP3 and other KChIPs (1-4). All the isoforms are expressed in the brain, whereas in the heart, KChIP2 is the isoform that is mainly expressed, where it regulates both the current generated by the activation of the KV4.3 channels and the current generated by the CaV1.2 channels. Various heart diseases, such as cardiac hypertrophy, present a decreased Ito. Moreover, it has been described that mice lacking KChIP2 are more susceptible to generate ventricular arrhythmias.
Taking into account the processes in which the KChIP2 protein is involved, it would be extremely useful to have compounds able to modulate this protein in order to treat diseases in which KChIP2 expression is altered, for example the treatment of heart diseases such as cardiac hypertrophy and heart failure (Grubb et al. Front Physiol. 2012; 3: 118).
Patent document US2008/0039442 describes a series of compounds which interact with the KV4.3 potassium channel for the treatment of heart diseases such as arrhythmia or hypertension, as well as nervous system diseases, such as epilepsy. Patent document WO2008/135447 describes a series of benzamides as BK channel and chloride channel modulators. None of these documents mentions KChIP2 protein.
The present invention relates to series of compounds having the capacity to modulate KChIP2 function and to affect the transient outward K+ current in cardiomyocytes, as demonstrated in the examples. Taking into account that the down-regulation of KChIP2 is associated with the onset of various heart diseases and that the up-regulation of KChIP2 prevents the development of cardiac hypertrophy in animal models, the compounds of the invention, which act as modulators of this protein, are useful in the treatment of heart diseases presenting a decrease in the transient outward K+ current.
In a first aspect, the invention relates to a compound of formula I):
wherein:
R1 and R2 are independently selected from H, OH, —O-aryl, halogen, aryl or heteroaryl, wherein said aryl or heteroaryl groups can be optionally substituted with (C1-C6) alkyl, —OH, (C3-C6) cycloalkyl, —O—(C1-C6) alkyl or halogen;
n has a value of 1 or 2;
Ar is selected from the following groups:
wherein R3 is selected from —OH or —O—(C1-C6)-alkyl; R4 is selected from H, halogen, —O—(C1-C6)-alkyl, phenyl optionally substituted with (C1-C6) alkyl; R5 is selected from H or phenyl optionally substituted with (C1-C6) alkyl,
or the salts, isomers or solvates thereof, for use in the treatment of heart diseases such as heart arrhythmia, myocardial ischemia, myocardial infarction, cardiac hypertrophy or cardiomyopathy.
In a preferred embodiment, Ar is the following group:
wherein R3 is OH, R4 is halogen, preferably Br, and R5 is H.
In a more preferred embodiment, the compound of formula (I) is 4-bromo-2-[2-(3,4-dichlorophenyl)acetylamino]benzoic acid (32bis).
In a preferred embodiment, the compound of the invention for use as described above is the compound of formula (Ia):
wherein R1, R2 and n are defined as above, or the salts, isomers or solvates thereof.
In a more preferred embodiment, in the compound (la) for use described above, R1 is selected from O-phenyl, phenyl, quinoline or pyridine, wherein said phenyl is optionally substituted with a group which is selected from (C1-C4) alkyl, —OH or (C3) cycloalkyl, and said pyridine is optionally substituted with a group which is selected from —O—(C1-C4) alkyl, —OH or halogen and R2 is H.
In an even more preferred embodiment, the compound (la) for use as described above is selected from the following list:
In another more preferred embodiment, in the compound (la) for use as described above, R1 is H and R2 is selected from O-phenyl, phenyl, quinoline or pyridine, wherein said phenyl is optionally substituted with a group which is selected from (C1-C4) alkyl, —OH or (C3) cycloalkyl, and said pyridine is optionally substituted with a group which is selected from —O—(C1-C4) alkyl, —OH or halogen.
In an even more preferred embodiment, the compound (la) for use as described above is selected from the following list:
In another preferred embodiment, in the compound (Ia) for use as described above, R1 and R2 are chlorine.
In a more preferred embodiment, the compound (Ia) for use as described above is selected from the following list:
In another preferred embodiment, in the compound (Ia) for use as described above, R1 and R2 are —OH.
In a more preferred embodiment, the compound (la) for use as described above is 4-chloro-2-[2-(3,4-dihydroxyphenyl)acetylamino]benzoic acid, (15bis).
In another preferred embodiment, the compound of the invention for use as described above is the compound of formula Ib):
wherein R1, R2 and n are defined as in claim 1, or the salts, isomers or solvates thereof.
In a more preferred embodiment, in the compound (Ib) for use described above, R1 is selected from O-phenyl, chlorine, phenyl, quinoline or pyridine, wherein said phenyl is optionally substituted with a group which is selected from (C1-C4) alkyl, —OH or (C3) cycloalkyl and said pyridine is optionally substituted with a group which is selected from —O—(C1-C4) alkyl, —OH or halogen and R2 is H.
In an even more preferred embodiment, the compound (Ib) for use as described above is selected from the following list:
In another more preferred embodiment, in the compound (Ib) for use as described above, R1 is H and R2 is selected from O-phenyl, chlorine, phenyl, quinoline or pyridine, wherein said phenyl is optionally substituted with a group which is selected from (C1-C4) alkyl, —OH or (C3) cycloalkyl and said pyridine is optionally substituted with a group which is selected from —O—(C1-C4) alkyl, —OH or halogen.
In an even more preferred embodiment, the compound (Ib) for use as described above is selected from the following list:
In another more preferred embodiment, in the compound (Ib) for use as described above, R1 and R2 are chlorine.
In an even more preferred embodiment, the compound (Ib) for use as described above is selected from the following list:
In another preferred embodiment, the compound of the invention for use as described above is the compound of formula (Ic):
wherein R4, R5 and n are defined as above, or the salts, isomers or solvates thereof.
In a more preferred embodiment, in the compound (Ic) for use as described above, R4 and R5 are independently selected from H, O—(C1-C4) alkyl or phenyl optionally substituted with a (C1-C4) alkyl.
In an even more preferred embodiment, the compound (Ic) for use as described above is selected from the following list:
Throughout the description and the claims, the word “comprises” and its variants do not intend to exclude other technical features, additives, components or steps. For persons skilled in the art, other objects, advantages and characteristics of the invention may be inferred from both the description and the embodiment of the invention. The following examples and figures are provided by way of example and are not intended to limit the present invention.
The compounds of general formula (I) of the present invention, can be synthesized in two steps following general methods A-D, depending on the possible substituents. In methods A-C, the first step consists of forming the necessary acid chlorides; and the second step consists of generating the amide, by means of reacting the different acid chlorides and the amine of interest. Method D consists of using peptide coupling agents. These methods are described in detail below:
2.4 mmol of oxalyl chloride and a drop of DMF are added, as a catalyst, to a solution of the corresponding carboxylic acid (1 mmol) in anhydrous THF (3 ml) at 0° C. The reaction mixture is stirred for two hours at room temperature. The acid chloride formed is dissolved in anhydrous THF (3 ml) and the corresponding amine (1.1 mmol) is added. Then, 3 equivalents of anhydrous Et3N (3 mmol) at 0° C. are added dropwise and it is stirred overnight at room temperature. The solvent is removed under vacuum and the crude reaction product is suspended in water, acidified with 1N HCl to pH=3 or 4, extracted with AcOEt and washed with a saturated solution of NaCl (3×15 ml). The organic phase is dried over Na2SO4 and concentrated under vacuum. As indicated in each case, the resulting residue is purified by medium-pressure chromatography or by crystallization.
The process for synthesizing the acid chloride is the one described in method A. Amide formation is carried out by means of heating in a microwave at 100° C. for 5 min using THF as solvent.
A solution of the corresponding carboxylic acid (0.75 mmol) in thionyl chloride (1.5 ml) is heated under reflux for 6 h. After this time, the excess thionyl chloride is evaporated to dryness. Then, the residue is dissolved in anhydrous THF (2 ml), and the corresponding amine (0.5 mmol) and propylene oxide (7.5 mmol) are added to the solution. The reaction is stirred at room temperature overnight. Lastly, the excess solvent is removed under vacuum and the solid formed is washed with water. The synthesized produce is purified by successive washes with the suitable solvent or by means of medium-pressure chromatography.
2.2 mmol of DIPEA or NMM are added to a solution of the corresponding amine (0.7 mmol) in DMF (2 ml). The solution is stirred at room temperature for 10 min. Then, a coupling agent (1.1 mmol, HATU, COMU, PyAOP-HOAt, EDC, DIC, HOBt) and the corresponding acid (1.1 mmol) are added. After 12 h of stirring at room temperature, the solvent is removed at low pressure. The crude reaction product is suspended in water, acidified with 1N HCl to pH=3 or 4, extracted with AcOEt (3×15 ml) and washed with a saturated solution of NaCl (3×15 ml). The organic phase is dried over Na2SO4 and the solvent is evaporated to dryness. The resulting residue is purified by medium-pressure chromatography.
Functionalization of the Aryl Ring. General Process.
Cross-coupling technology allows the functionalization of an aryl ring through reactions catalyzed by a transition metal. For example, a Suzuki coupling can be carried out using aryl bromide and a boronic acid coupling partner. Alternatively, couplings between a terminal acetylene and an aryl halide can be carried out by means of the Sonogashira reaction.
a. Suzuki Coupling
An aryl halide (0.4 mmol), the corresponding boronic acid derivative (0.6 mmol), K2CO3 (2.6 mmol), [Pd(PPh3)4] (2% by weight) and 7 ml of a THF/H2O (4/1) mixture are added in a microwave tube. The reaction mixture is purged with argon and heated by irradiating at 125° C. for 15 min in a microwave reactor. Then, an additional 0.6 mmol of the corresponding boronic acid are added and the described process is repeated. The solvent is removed to dryness, water is added and extracted with DCM (3×10 ml). The organic phases are washed with H2O (3×10 ml), dried over Na2SO4, and concentrated at low pressure. The crude reaction product is purified by medium-pressure chromatography.
b. Sonogashira Reaction
The corresponding brominated derivative (0.22 mmol), Cul (0.06 mmol), [Pd(PPh3)4] (20% by weight), Et3N (1.74 mmol), trimethylsilylalkyne (0.67 mmol) and 1.5 ml of a THF/DMF (10/3) mixture are added in a sealed tube with a 25 ml capacity. The reaction mixture is heated at 45° C. for 12 h. The solvent is evaporated to dryness and the residue is extracted with AcOEt (3×10 ml). The organic phases are washed with H2O (3×10 ml), dried over Na2SO4, and concentrated at low pressure. The crude reaction product is purified by medium-pressure chromatography (hexane/AcOEt).
Ester Group Saponification. General Process
A 2N NaOH solution (0.2 ml) is added dropwise to a solution of the corresponding ester (0.09 mmol) in 1.2 ml of THF and 0.6 ml of MeOH. After 12 h of stirring at room temperature, the solvent is removed at low pressure, water is added and it is acidified with 1N HCl to pH 3 or 4. The aqueous phase is extracted with AcOEt (3×10 ml). The organic extracts are washed with water and a saturated solution of NaCl, dried over Na2SO4, the solvent is removed to dryness and lyophilized. The product is obtained in pure form without requiring additional purifications.
Solid. Yield 66%. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 11.37 (s, 1H, NHCO), 8.64 (d, 1H, J=2.2 Hz, H3), 7.95 (d, 1H, J=8.5 Hz, H6), 7.63 (m, 4H, H2′, H4′, H6″, H2″), 7.50-7.33 (m, 5H, H5, H3″, H5″, H5″, H6″), 7.20 (dd, 1H, J=8.6, 2.2 Hz, H4″), 3.87 (s, 2H, CH2O). 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 170.0 (CONH), 168.7 (COOH), 141.8 (C2), 140.45 (C4), 140.0 (C1″), 138.4 (C3′), 135.2 (C1′), 132.8 (C6), 129.8 (C4″), 128.9 (2C, C3″, C5″), 128.6 (C6′), 128.1 (C2′), 127.5 (C5′), 126.7 (2C, C2″, C6″), 125.4 (C5), 122.6 (C4′), 119.1 (C3), 115.2 (C1), 44.6 (CH2CO). Agilent HPLC (gradient 50-95% of A in B, 20 min): tR=8.18 min.
White syrup. Yield 42%. 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 11.31 (s, 1H, NHCO), 8.64 (d, 1H, J=2.2 Hz, H3), 7.95 (d, 1H, J=8.5 Hz, H2′), 7.73-7.50 (m, 4H, H6, H6″, H2″, H4′) 7.48-7.15 (m, 5H, H5, H5′, H6′, H3″, H5″), 3.86 (s, 2H, CH2CO), 2.60 (t, 2H, J=7.7 Hz, 4″1CH2), 1.65-1.50 (m, 2H, 4″2CH2), 1.32 (h, 2H, J=7.3 Hz, 4″3CH2), 0.90 (t, 3H, J=7.3 Hz, 4″CH3). 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 170.0 (CONH), 168.7 (COOH), 141.9 (C2), 141.7 (C4), 140.4 (C3′), 138.5 (C1″), 137.3 (C4″), 135.1 (C1′), 132.8 (C6), 129.2 (C6′), 128.9 (2C, C2″, C6″), 128.3 (C2′), 127.8 (C5′), 126.6 (2C, C3″, C5″), 125.2 (C5), 122.6 (C4′), 119.1 (C3), 115.0, (C1), 44.6 (CH2CO), 34.4 (4″1 CH2), 33.1 (4″2CH2), 21.8 (4″3CH2), 13.8 (4″CH3). LC-MS: 422.2 ([M+H]+).
Solid (60 mg). Yield 75%. HPLC (Sunfire): tR=2.82 min (gradient of 70 to 95% of solvent A in B, 10 min). HPLC (Eclipse): tR=10.49 min (gradient of 50 to 100% of solvent A in B, 20 min).1H-NMR (400 MHz, DMSO-d6) δ: 11.86 (br s, 1H, NHCO), 8.61 (d, 1H, J=2.2 Hz, H3), 7.95 (d, 1H, J=8.5 Hz, H6), 7.63 (m, 1H, H2′), 7.59 (d, 2H, J=8.2 Hz, H2″, H6″), 7.54 (s, 1H, H4′), 7.42 (t, 1H, J=7.6 Hz, H5′), 7.33 (m, 1H, H6′), 7.30 (d, 2H, J=8.1 Hz, H5″, H3″), 7.16 (dd, 2H, J=8.5, 2.2 Hz, H5′), 3.83 (s, 2H, CH2CO), 2.64 (q, 2H, J=7.6 Hz, CH2), 1.21 (t, 3H, J=7.6 Hz, CH3) ppm. 13C-NMR (75 MHz, DMSO-d6) δ: 169.9 (CO2H), 168.6 (CONH), 143.1 (C2), 141.8 (C4), 140.4 (C4″), 137.7 (C3′), 137.4 (C1″), 135.3 (C1′), 132.8 (C6), 129.1 (C6′), 128.3 (3C, C2″, C6″, C2′), 128.2 (C5), 127.7 (C5′), 126.6 (2C, C3″, C5″), 125.1 (C4′), 122.3 (C3), 118.8 (C1), 44.6 (CH2CO), 27.8 (CH2), 15.6 (CH3) ppm. EM (ES−): m/z 392.27 (M−H)+. Chemical Formula: C23H20ClNO3. Elemental Analysis Calculated: C, 70.14; H, 5.12; Cl, 9.00; N, 3.56; O, 12.19.
Solid (66 mg). Yield 66%. HPLC (Sunfire): tR=7.14 min (gradient of 60 to 95% of solvent A in B, 10 min). HPLC (Eclipse): tR=12.18 min (gradient of 50 to 100% of solvent A in B, 20 min).1H-NMR (400 MHz, DMSO-d6) δ: 11.37 (br s, 1H, NHCO), 8.64 (d, 1H, J=2.2 Hz, H3), 7.95 (d, 1H, J=8.6 Hz, H6), 7.64 (s, 1H, H2′), 7.60 (d, 2H, J=8.4 Hz, H6″, H2″), 7.56 (m, 1H, H4′), 7.48 (d, 2H, J=8.4 Hz, H3″, H5″), 7.43 (t, 1H, J=7.6 Hz, H5′), 7.32 (m, 1H, H6′), 7.20 (dd, 1H, J=8.6, 2.2 Hz, H5), 3.86 (s, 2H, CH2CO), 1.31 (s, 9H, CH3, tBu) ppm. 13C-NMR (75 MHz, DMSO-d6) δ: 170.0 (CO2H), 168.7 (CONH), 149.9 (C4″), 141.8 (C2), 140.3 (C4), 138.4 (C3′), 137.1 (C1″), 135.4 (C1″), 132.8 (C6), 129.1 (C6′), 128.3 (C5), 127.8 (C5′), 126.4 (2C, C2″, C6″), 125.7 (2C, C3″, C5″), 125.2 (C2′), 122.6 (C4′), 119.1 (C3), 115.2 (C1), 44.6 (CH2CO), 34.2 (C, tBu), 31.1 (CH3, tBu) ppm. EM (ES+): m/z 422.34 (M+H)+. Chemical Formula: C25H24ClNO3. Elemental Analysis Calculated: C, 71.17; H, 5.73; Cl, 8.40; N, 3.32; O, 11.38. Elemental Analysis Found: C, 70.99; H, 5.77; N, 3.59.
Solid (106 mg). Yield 82%. HPLC (Sunfire): tR=6.09 min (gradient of 50 to 95% of solvent A in B, 10 min). HPLC (Eclipse): tR=8.96 min (gradient of 50 to 100% of solvent A in B, 20 min). 1H-NMR (400 MHz, DMSO-d6) δ: 11.27 (br s, 1H, NHCO), 8.58 (d, 1H, J=2.2 Hz, H3), 7.97 (d, 1H, J=8.6 Hz, H6), 7.31 (m, 5H, H5, H6′, H3″, H4″, H5″), 7.21 (dd, 1H, J=8.6, 2.2 Hz, H2″), 7.10 (t, 1H, J=7.4 Hz, H4′), 6.96 (m, 3H, H3″, H6″, H5′), 6.81 (ddd, 1H, J=8.1, 2.1 Hz, H2′), 2.93 (t, 2H, J=7.4 Hz, CH2), 2.73 (t, 2H, J=7.4 Hz, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6) δ: 170.8 (CO2H), 168.7 (CONH), 156.7 (2C, C3′, C1″), 142.9 (C2), 141.8 (C4), 138.3 (C1′), 132.8 (C6), 130.0 (3C, C3″, C5″, C5′), 123.5 (C5), 123.3 (C4″), 122.5 (C6′), 119.1 (C3), 118.6 (C4′), 118.5 (2C, C2″, C6″), 116.4 (C2′), 115.2 (C1), 30.3 (2C, CH2CH2CO, CH2CO) ppm. EM (ES+): m/z 396.17
White solid. Yield 47%. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.27 (s, 1H, NHCO), 8.64 (d, 1H, J=2.1 Hz, H3), 7.96 (d, 1H, J=8.6 Hz, H6), 7.38 (m, 4H, H5, H2′, H6′, H5″), 7.20 (dd, 1H, J=8.5, 2.2 Hz, H3″), 7.15-7.10 (m, 1H, H4″), 7.03-6.97 (m, 4H, H5′, H3′, H2″, H6″), 3.78 (s, 2H, CH2CO). 13C-NMR 100 MHz, DMSO-d6) δ (ppm): 170.1 (CONH), 168.6 (COOH), 156.8 (C4′), 155.79 (C1″), 141.8 (C2), 138.4 (C4), 132.8 (C6), 131.3 (2C, C5″, C3″), 130.0 (2C, C2′, C6′), 129.6 (C1′), 123.3 (C5), 122.6 (C4″), 119.0 (C3), 118.9 (2C, C6″, C2″), 118.4 (2C, C3′, C5′), 115.1 (C1), 43.7 (CH2CO). HPLC (gradient of 50-95% of A in B, 10 min): tR=5.63 min. LC-MS: 382.2 ([M+H]+). (M+H)+.
Solid (12 mg). Yield 29%. HPLC (Sunfire): tR=7.02 min (gradient of 60 to 95% of solvent A in B, 10 min). HPLC (Eclipse): tR=12.40 min (gradient of 50 to 100% of solvent A in B, 20 min).1H-NMR (400 MHz, DMSO-d6) δ: 1H-NMR (400 MHz, DMSO-d6) δ: 11.47 (br s, 1H, NHCO), 8.62 (d, 1H, J=2.2 Hz, H3), 7.96 (d, 1H, J=8.5 Hz, H6), 7.63 (d, 2H, J=8.2 Hz, H2′, H6′), 7.59 (d, 2H, J=8.5 Hz, H2″, H6″), 7.47 (d, 2H, J=8.4 Hz, H3″, H5″), 7.42 (d, 2H, J=8.2 Hz, H3′, H5′), 7.20 (dd, 2H, J=8.6, 2.2 Hz, H5), 3.81 (s, 2H, CH2CO), 1.31 (t, 3H, J=7.6 Hz, CH3) ppm. 13C-NMR (75 MHz, DMSO-d6) δ: 170.0 (CO2H), 168.7 (CONH), 149.8 (C4″), 141.8 (C2), 138.7 (C4), 138.2 (C4′), 136.9 (C1″), 133.5 (C1″), 132.8 (C6), 130.1 (2C, C2″, C6″), 126.6 (2C, C3′, C5′), 126.2 (2C, C2′, C6′), 125.7 (2C, C3″, C5″), 122.6 (C5), 119.0 (C3), 115.5 (C1), 44.2 (CH2CO), 34.2 (C, tBu), 31.3 (CH3, tBu) ppm. EM (ES−): m/z 420.35 (M−H)+.
Solid (19.5 mg). Yield 47%. HPLC (Sunfire): tR=8.54 min (gradient of 50 to 95% of solvent A in B, 10 min). HPLC (Eclipse): tR=17.66 min (gradient of 5 to 100% of solvent A in B, 20 min).1H-NMR (400 MHz, DMSO-d6) δ: 11.42 (br s, 1H, NHCO), 8.63 (d, 1H, J=2.2 Hz, H3), 7.95 (d, 1H, J=8.4 Hz, H6), 7.93 (s, 1H, H2′), 7.73 (s, 1H, H2″), 7.70 (d, 1H, J=4.1 Hz, H4′), 7.69 (m, 1H, H6′), 7.64 (dd, 1H, J=7.7, 1.6 Hz, H6″), 7.45 (t, 1H, J=7.6 Hz, H5′), 7.40 (d, 1H, J=7.7 Hz, H5″), 7.19 (dd, 1H, J=8.6, 2.2 Hz, H5), 3.87 (s, 2H, CH2CO) ppm. 13C-NMR (75 MHz, DMSO-d6) δ: 169.8 (CO2H), 168.6 (CONH), 141.8 (C2), 140.6 (C4), 138.2 (C3′), 137.7 (C1″), 135.4 (C1′), 132.8 (C6), 131.7 (C3″), 131.0 (C6′), 130.2 (C6″), 129.6 (C2″), 129.3 (C4″), 128.5 (C2′), 128.2 (C5″), 126.9 (C5′), 125.5 (C5), 122.6 (C4′), 119.0 (C3), 115.5 (C1), 44.3 (CH2CO) ppm. EM (ES−): m/z 432.99 (M−H)+.
Example 2. Tests of the effects of the compounds on the KV4.3/KChIP2 and KV4.3/KChIP2/DPP6 currents generated after the activation of KV4.3/KChIP2 and KV4.3/KChIP2/DPP6 channels expressed in CHO cells.
The compounds synthesized according to this invention have been evaluated in vitro in voltage clamp tests in CHO cells transiently transfected with cDNA encoding KV4.3 alone or KV4.3 in the presence of KChIP2 (KV4.3+KChIP2) and DPP6 (KV4.3+KChIP2+DPP6) using the whole-cell configuration of the patch-clamp technique. Some of the compounds activate the current generated by the activation of KV4.3+KChIP2 channels. Thus, as observed in
| Number | Date | Country | Kind |
|---|---|---|---|
| 18382890.4 | Dec 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/083432 | 12/3/2019 | WO | 00 |
