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Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.

Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ - J. Med. Chem. (2011)

Bottom Line: Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol.For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J.Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, 40126 Bologna, Italy.

ABSTRACT
The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

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Compound efficacy on ΔF508-CFTR. The efficacy is obtained from dose–response relationships of YFP fluorescence experiments (mean ± SEM, n = 3).
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fig1: Compound efficacy on ΔF508-CFTR. The efficacy is obtained from dose–response relationships of YFP fluorescence experiments (mean ± SEM, n = 3).

Mentions: FRT cells expressing ΔF508-CFTR were incubated at 27 °C for 24 h to rescue the mutant protein from ER, thus improving its targeting to the plasma membrane. Subsequently the cells were stimulated with forskolin (20 μM) in the presence and absence of 1,4-DHPs at different concentrations. Under these conditions, the cAMP activating pathway is saturated by the high forskolin concentration. Therefore, any increase in ΔF508-CFTR activity caused by a compound above the level reached with forskolin alone can be attributed to a potentiator-like activity. We tested 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines as well as 48, 49, and 50, identified as CFTR-selective potentiators from a previous study.13 We also included genistein as a non-1,4-DHP potentiator. Nifedipine, our reference compound, shows a maximal activity of 58 and Kd = 2.9 ± 0.4 μM. Compounds 48 [Kd = 0.37 ± 0.07 μM], 49 [Kd = 0.17 ± 0.03 μM], and 50 [Kd = 0.40 ± 0.05 μM] show efficacy comparable to that of nifedipine but, as reported previously,13 with greatly improved potency. In particular, 49 has 17-fold increased potency relative to nifedipine. Among 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines, compounds 23, 24, 30, 32, 35, 37, 40–47 are inactive. In contrast, as shown in Figure 1, compounds 17, 20, 21, 38, and 39 effectively induce CFTR activity, with a maximal effect elicited at 20 μM comparable to that of nifedipine and 48–50. However, the 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines appear significantly less potent given the small activity induced at 0.2 μM. There are compounds such as 18 with apparently high potency [Kd = 0.18 ± 0.03] but with partial activity (Emax = 42) (Table 2).


Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.

Budriesi R, Ioan P, Leoni A, Pedemonte N, Locatelli A, Micucci M, Chiarini A, Galietta LJ - J. Med. Chem. (2011)

Compound efficacy on ΔF508-CFTR. The efficacy is obtained from dose–response relationships of YFP fluorescence experiments (mean ± SEM, n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108470&req=5

fig1: Compound efficacy on ΔF508-CFTR. The efficacy is obtained from dose–response relationships of YFP fluorescence experiments (mean ± SEM, n = 3).
Mentions: FRT cells expressing ΔF508-CFTR were incubated at 27 °C for 24 h to rescue the mutant protein from ER, thus improving its targeting to the plasma membrane. Subsequently the cells were stimulated with forskolin (20 μM) in the presence and absence of 1,4-DHPs at different concentrations. Under these conditions, the cAMP activating pathway is saturated by the high forskolin concentration. Therefore, any increase in ΔF508-CFTR activity caused by a compound above the level reached with forskolin alone can be attributed to a potentiator-like activity. We tested 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines as well as 48, 49, and 50, identified as CFTR-selective potentiators from a previous study.13 We also included genistein as a non-1,4-DHP potentiator. Nifedipine, our reference compound, shows a maximal activity of 58 and Kd = 2.9 ± 0.4 μM. Compounds 48 [Kd = 0.37 ± 0.07 μM], 49 [Kd = 0.17 ± 0.03 μM], and 50 [Kd = 0.40 ± 0.05 μM] show efficacy comparable to that of nifedipine but, as reported previously,13 with greatly improved potency. In particular, 49 has 17-fold increased potency relative to nifedipine. Among 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines, compounds 23, 24, 30, 32, 35, 37, 40–47 are inactive. In contrast, as shown in Figure 1, compounds 17, 20, 21, 38, and 39 effectively induce CFTR activity, with a maximal effect elicited at 20 μM comparable to that of nifedipine and 48–50. However, the 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines appear significantly less potent given the small activity induced at 0.2 μM. There are compounds such as 18 with apparently high potency [Kd = 0.18 ± 0.03] but with partial activity (Emax = 42) (Table 2).

Bottom Line: Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol.For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J.Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, 40126 Bologna, Italy.

ABSTRACT
The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

Show MeSH
Related in: MedlinePlus