Cystic Fibrosis: A New Target for 4-Imidazo[2,1-<i>b</i>]thiazole-1,4-dihydropyridines

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 Ca²⁺ 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-<i>b</i>]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 <b>17</b>, <b>18</b>, <b>20</b>, <b>21</b>, <b>38</b>, and <b>39</b> as 1,4-DHPs with an interesting profile of activity

Ligand Based Approach to L‑Type Calcium Channel by Imidazo[2,1‑<i>b</i>]thiazole-1,4-Dihydropyridines: from Heart Activity to Brain Affinity

The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and their selectivity on Ca_v1.2 and Ca_v1.3 isoforms, we performed binding studies on guinea pig atrial and ventricular membranes on intact cells expressing the cloned Ca_v1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Ca_v1.2 and/or Ca_v1.3, molecular modeling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure–activity relationship of the 4-imidazo­[2,1-<i>b</i>]­thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level

Substituted 3-(5-Imidazo[2,1-<i>b</i>]thiazolylmethylene)-2-indolinones and Analogues: Synthesis, Cytotoxic Activity, and Study of the Mechanism of Action

The synthesis of substituted 3-(5-imidazo­[2,1-<i>b</i>]­thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly