Virtual screening for novel openers of pancreatic K(ATP) channels

Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward, six molecules were selected as templates for similarity searches: similarity scores, obtained toward these templates, were calculated with the GRIND, FLAP, and TOPP approaches, which differently encode structural information into potential pharmacophores. In this way, we obtained 32 hit candidates, 16 via GRIND and eight each via FLAP and TOPP. For biological testing of the hit candidates, their effects on membrane potentials in HEK 293 cells expressing Kir6.2/SUR1 were studied. GRIND, FLAP, and TOPP all yielded hits, but no method top-ranked all the actives. Thus, parallel application of different approaches probably improves hit detection.     

The pre-clinical assessment of rapamycin-eluting, durable polymer-free stent coating concepts

All four currently FDA-approved drug-eluting stents (DESs) contain a durable polymeric coating which can negatively impact vascular healing processes and eventually lead to adverse cardiac events. Aim of this study was the pre-clinical assessment of two novel rapamycin-eluting stent (RES) coating technologies that abstain from use of a durable polymer. Two distinctive RES coating technologies were evaluated in vitro and in the porcine coronary artery stent model. The R-poly(S) stent platform elutes rapamycin from a biodegradable polymer that is top coated with the resin shellac to minimize the amount of polymer. The R-pro(S) stent platform allows dual drug release of rapamycin and probucol, blended by shellac. HPLC-based determination of pharmacokinetics indicated drug release for more than 28 days. At 30 days, neointimal formation was found to be significantly decreased for both DESs compared to bare-metal stents. Assessment of vascular healing revealed absence of increased inflammation in both DESs, which is commonly observed in DES with non-erodible polymeric coating. In conclusion, the pre-clinical assessment of RESs with resin-based or dual drug coating indicated an adequate efficacy profile as well as a beneficial effect for vascular healing processes. These results encourage the transfer of these technologies to clinical evaluation.     

The hydrophobic fragmental constant approach forcalculating log P in octanol/water and aliphatic hydrocarbon/water systems

We have investigated the relationship between drug retention in immobilized liposome partitioning chromatography and liposome partitioning and found a strong linear correlation. Separate linear relationships were found depending on the charge of the compound when liposome chromatographic measurements were related to the octanol/water partition coefficients. We have also investigated the importance of the water/octanol partition coefficient in quantitative structure–property relationships related to drug transport properties. The studies show that the inclusion of a parameter related to lipophilicity causes only, at best, a marginal increase in internal predictivity and, at worst, a decrease in external predictivity. The studies also show that parameters related to hydrogen bonding, polarizability and size are important properties that need to be included in quantitative models for drug transport processes. We believe that the use of multivariate characterizations of compounds based on non-composite parameters may result in better and more predictive models compared with models based on parameters of a more composite nature when investigating the possibilities to establish quantitative structure–property relationships. This revised version was published online in August 2006 with corrections to the Cover Date.     

Putative therapeutic applications of calmodulin antagonists

Calmodulin is the most important intracellular receptor protein for the second messenger calcium. The calcium-calmodulin complex regulates a number of physiological processes. An increasing number of pharmaceutical products is reported to interfere with the calcium-calmodulin complex. Despite the fact that the precise mechanisms of action of these so-called calmodulin antagonists await further clarification, reports accumulate in the literature indicating a broadening spectrum of putative therapeutic applications of calmodulin antagonists. Some of these applications, such as in cell proliferation, hypertension, congestive heart failure, arrhythmia and gastro-intestinal disorders, are discussed in the present review.     

Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium

On isotonically contracting cat papillary muscles analysis, a comparison of the effects of the optical isomers of verapamil and D 600 and the racemic drugs was performed. 1. (-)-verapamil (0.2-3.0 mug/mo) and (-)-D-600 (0.1 mug/ml-3.0 mug/ml) leave the steady state contraction amplitudes nearly unchanged at 6/min, but produce a strong depression at 60/min. (-)-D 600 is about 8 times as effective as (-)-verapamil. The (+)-isomers exert only a moderate negative inotropic effect (particularly at low frequencies). 2. Increase of [Ca2+]O does not restitute the normal amplitude-frequency relationship during exposure to either the (-)-isomers or the (+)-isomers. 3. The (-)-isomers lead to typical biphasic staircases after step changes of frequency. A fast negative staircase occurs first followed by a rather slowly developing positive staircase. In contrast, the (+)-isomers have little influence on the usual staircase pattern. 4. The strength-interval relationship for single test contractions elicited after frequent conditioning stimulation indicated that the (-)-isomers probably slow the restitution of intracellular Ca-reavailability. The (+)-isomers have no such effects. 5. The effects produced by the (+/-)-compounds correspond qualitatively to those of the (-)-isomers. 6. The very different patterns of inotropic actions observed indicate that the (-)- and (+)-isomers of verapamil and D 600 probably interfere with cardiac excitation-contraction coupling at different sites.     

Importance of nitrile substitution for the Ca antagonistic action

The effects of verapamil congeners, a) obtained by exchange of the nitrile substituent and b) a structural isomer, on the contractile activity were investigated in isotonically contracting cat papillary muscle. Results indicate that the nitrile substituent is essential for the negative inotropic action of verapamil. Investigations with an ortho disubstituted structural isomer of verapamil showed an unchanged mode of action, while potency is decreased. These findings can be explained on the basis of differences in the steric and electronic properties of the molecules under consideration.     

Interactions of antiarrhythmics with artificial phospholipid membranes

Binding of antiarrhythmics to phospholipids has been quantified by measuring the drug-induced fluorescence increase in 8-anilino-1-napthalenesulfonate (ANS)-treated phosphatidylcholine membranes. The ability of test compounds to increase fluorescence intensity to 50% varies between 1.3 and 88 X 10(-6) M, exhibiting a potency ratio of 1.8 log units. The antiarrythmics tested in this study exhibited a wide spectrum of lipophilicity ranging between sigma f = 6.66 for the most lipophilic compound asocainol, to sigma f = 1.21 for the most hydrophilic compound procainamide. The pKa values ranged from 10.80 for quinacainol to 6.26 for ethmozine. Consequently, the test compounds are 99.9 to 6.8% protonated at physiological pH. Binding of antiarrythmics to phosphatidylcholine membranes appears to be determined mainly by their lipophilicity (r = 0.91), irrespective of the pKa, as demonstrated for ethmozine and lidocaine which showed an excellent fit to the regression line. Binding of a variety of antiarrhythmics (n = 8) to phosphatidylcholine appeared to correlate significantly with the mean daily dosage for these drugs (r = 0.97).     

Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide AT1, AT2, and AT1/AT2 angiotensin II receptor antagonists

About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.     

The impact of lipophilicity in drug research: a case report on beta-blockers

The key importance of lipophilicity in bio-studies is discussed for beta-blockers. Examples of their lipophilicity-dependent pharmacological properties including pharmacokinetic, pharmacodynamic and clinical aspects are reviewed. Comprehensive lipophilicity compilations of beta-blockers are lacking so far. LogP calculations with 10 programs for 30 clinically relevant beta-blockers are presented for the first time in this review.