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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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(a) Comparison of potencies of different biological parameters for compounds with the best, interesting profile. (b) Reference compounds. Data are expressed as −log potency ± CL.
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fig3: (a) Comparison of potencies of different biological parameters for compounds with the best, interesting profile. (b) Reference compounds. Data are expressed as −log potency ± CL.

Mentions: Our study confirms the possibility in the development of 1,4-DHPs with increased activity and selectivity as potentiators of mutant CFTR and, at the same time, reduced activity as inhibitors of voltage-dependent Ca2+ channels of the cardiovascular system and smooth muscle of nonvascular tissues (see Figure 3). This is highly desirable for developing drugs able to correct the basic defect in cystic fibrosis while having minimal side effects. However, the 1,4-DHPs evaluated in this study still keep some activity in nonepithelial cells. This may be caused by residual activity on some types of Ca2+ channels and/or expression of CFTR in cardiac and smooth muscle cells. To further minimize undesired effects, it is possible to generate novel 1,4-DHPs based on SAR obtained from the present and previous studies. In general the results suggest that the core imidazo[2,1-b]thiazole is confirmed as a suitable heterocycle to explore new potentiators of mutant CFTR. Of further interest is the effect of the imidazo[2,1-b]thiazole substitution pattern on the profile of biological action. CFTR-selective potentiators might be better achieved by a phenyl ring with appropriate substituents at the 6-position of the imidazo[2,1-b]thiazole, while the substituents at the 2-position can influence cardiovascular parameters to the same extent. In addition, systemic effects may be further minimized by considering delivery of 1,4-DHP potentiators via aerosol.


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)

(a) Comparison of potencies of different biological parameters for compounds with the best, interesting profile. (b) Reference compounds. Data are expressed as −log potency ± CL.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: (a) Comparison of potencies of different biological parameters for compounds with the best, interesting profile. (b) Reference compounds. Data are expressed as −log potency ± CL.
Mentions: Our study confirms the possibility in the development of 1,4-DHPs with increased activity and selectivity as potentiators of mutant CFTR and, at the same time, reduced activity as inhibitors of voltage-dependent Ca2+ channels of the cardiovascular system and smooth muscle of nonvascular tissues (see Figure 3). This is highly desirable for developing drugs able to correct the basic defect in cystic fibrosis while having minimal side effects. However, the 1,4-DHPs evaluated in this study still keep some activity in nonepithelial cells. This may be caused by residual activity on some types of Ca2+ channels and/or expression of CFTR in cardiac and smooth muscle cells. To further minimize undesired effects, it is possible to generate novel 1,4-DHPs based on SAR obtained from the present and previous studies. In general the results suggest that the core imidazo[2,1-b]thiazole is confirmed as a suitable heterocycle to explore new potentiators of mutant CFTR. Of further interest is the effect of the imidazo[2,1-b]thiazole substitution pattern on the profile of biological action. CFTR-selective potentiators might be better achieved by a phenyl ring with appropriate substituents at the 6-position of the imidazo[2,1-b]thiazole, while the substituents at the 2-position can influence cardiovascular parameters to the same extent. In addition, systemic effects may be further minimized by considering delivery of 1,4-DHP potentiators via aerosol.

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