Letters in Drug Design & Discovery - Volume 3, Issue 4, 2006

Large-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cells, where they play an essential role in the regulation of cell excitability and function. BK channel openers constitute a heterogeneous group of organic compounds being able to activate BK channels and having a wide therapeutic potential for the treatment of different neurological, urological and cardiovascular diseases. This review addresses the novel research on BK channels as drug targets as well as it reports recent developments in the chemistry of BK channel openers and in the chemical structural aspects determining their activity.

Malaria is one of the most dangerous diseases affecting primarily poor people of tropical and subtropical regions of the world with a worldwide death toll of over 1.5 million a year coupled with increasing resistance to common antimalarial drugs, such as chloroquine and mefloquine, justifies WHO's appeal for search and delivery of novel antimalarial drugs as quick as possible. This review describes how by using in silico (computational) methods, specifically three-dimensional QSAR pharmacophores developed from known antimalarial compounds could be used as screening tools for identification of potential new candidates through search of virtual compound libraries. The review is based on two select examples of pharmacophore models published by us recently: the antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) and the tricyclic antidepressants as chloroquine (CQ) resistance reversal agents. The model developed from the tryptanthrins was found to correlate well with this class of compounds and predictive for other known antimalarials of different chemical classes, such as quinolines, chalcones, rhodamine dyes, Pfmrk (malarial cyclin dependent kinase inhibitors), malarial FabH (KASIII) inhibitors, and plasmepsin inhibitors. Similarly, the CQ-resistance reversal model too is found to be fairly well correlated for the tricyclic antidepressants and predictive for a variety of other known CQ-resistance reversal agents. The pharmacophores allowed search and identification of potent antimalarial compounds from in-house databases and enabled custom designed synthesis of new potent analogues.

Probenecid is used as a uricosuric agent in the treatment of chronic gout and as an adjunct to enhance antibiotic levels in the blood. For research purposes, it is used as a prototypic inhibitor of organic anion transporters and MRPs, including MPR2. The purpose of this research is to study the interaction of probenecid with two other important transporters of the ATP-binding cassette family, Breast Cancer Resistance Protein (BCRP) and P-glycoprotein. These drug efflux transporters are present in the intestine, liver and other organs, and they affect the bioavailability of many compounds. Using the polarized canine kidney cell line MDCK-II and its human MDR1-, BCRP- and murine Bcrp1-transduced subclones, we found that probenecid is transported by mouse Bcrp1 and human BCRP, but not by P-glycoprotein. In addition, flow cytometry experiments showed that probenecid did not affect the accumulation of mitoxantrone in Bcrp1- and BCRPtransduced cells, indicating that this compound was not an effective BCRP/Bcrp1 inhibitor at the concentrations used. We conclude that probenecid is a good substrate of BCRP/Bcrp1, suggesting potential interaction with BCRP/Bcrp1 inhibitors.

Two epigenetic events that are associated with transcriptional silencing in carcinogenesis include hypermethylation of CpG islands near gene promoter regions and changes in chromatin conformation involving histone acetylation. Pharmacologic targeting of these epigenetic processes and upregulation of genes involving fundamental cellular pathways have become a new therapeutic strategy in the treatment of hematopoietic malignancies.

Mogroside I E1 (compound 3), a steroidal glycoside (i.e., mogroside) isolated from traditional Chinese medicinal plants (Momordica grosvenori) selectively inhibited the activities of animal DNA polymerases from mammals, fish and insects in vitro. The compound showed no effect on the activities of DNA polymerases from plants and procaryotes, and other DNA metabolic enzymes tested. Compound 3 also inhibited human cancer cell growth. Since parts of compound 3 such as mogrol (compound 1) and D-glucose (compound 2) did not influence the activities of any enzymes tested, the converted structure of compounds 1 and 2 might be important for DNA polymerase inhibition and the suppression of cancer cell growth. The other four mogrolal glycosides (i.e., compounds 4 - 7) did not influence the inhibition of DNA polymerase activity and human cancer cell proliferation. The relationship between the three-dimensional molecular structure of mogrol-based compounds and these inhibitory activities is discussed.

Farsenoid X receptor (FXR) is an attractive drug target due to its role in the regulation of cholesterol and bile acid levels. Hologram quantitative structure-activity relationships (HQSAR) were conducted on a series of FXR activators, and the final model obtained was used to predict the potency of 10 test set compounds. The predicted values were in good agreement with the experimental results.

Alzheimer's Disease (AD) is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. However, the pathogenesis of AD is still not clearly known. Current research in drug discovery for treatment of AD involves various targets, being only symptomatic, with the main therapeutic strategies based on "cholinergic hypothesis" and "amyloid cascade hypothesis". During the last decade, inhibitors of acetylcholinesterase (AChE) such as tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galanthamine (Reminyl®) have been launched. More recently, memantine (Ebixa®) has been emerged on the market as an N-methyl-D-aspartate (NMDA) receptor antagonist, which has been approved to be effective in the treatment of moderate to severe type of AD. In this review, we will focus on recent status of drug molecules for treatment of AD, currently either that in clinical practice, or still in clinical trials.

Two loaded nanoparticles, albendazole polybutylcyanoacrylate nanoparticles (ABZ-PBCA-NP) and albendazole polyvinylpyrrolidone. Polybutylcyanoacrylate nanoparticles (ABZ-PVP-PBCA-NP) were prepared by the emulsification-polymerization method. Tissue distribution and tissue targeting of ABZ-PBCA-NP in mice was studied. The drug-load mechanism of ABZ-PBCA-NP was studied by the equal-temperature absorption principle. The drug loaded in nanoparticle was coincident with the Langmuir adsorption equation. The dialyzed dynamic of albendazole from four formulations, ABZ-PBCA-NP, PVP-ABZ-PBCA-NP, ABZ suspension (SABZ) and ABZ liquid (LABZ), was investigated in vitro. ABZ-PBCA-NP and PVP-ABZ-PBCA-NP were suitable for the Higuchi and bi-exponent function respectively. The absorptive capability of the drug was enhanced when 4% PVP was added into the nanoparticle, and its release time was increased. The tissue distribution of albendazole in different drug vehicles was studied by isotope labeling experiment. Targeting index of albendazole in liver and spleen in mice was estimated at 11.4 and 3.9 after ig 3H-ABZ-PBCA-NP. The bioavailability of albendazole nanoparticle and suspension was 76.0% and 36.9%, respectively. The results have shown that the nanoparticle vehicles increase the albendazole bioavailability.

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Using a combined virtual screening approach, we have identified the pyrazoloquinazoline tricyclic system as a novel scaffold to design new kinase CK2 inhibitors.