Letters in Drug Design & Discovery - Volume 1, Issue 1, 2004

Rapid advances in the field of drug design have resulted over the last two decade in a growing number of high quality publications. Many of which cannot be published in a timely fashion because of limited number of fast publication journals with the result that publications of important and urgent results are often delayed by a year or more. There was, therefore, an acute need of a journal which would publish important revi Read More

To thwart phase II metabolism, Structure-Activity-Relationship (SAR) studies around the phenol of the potent glucocorticoid receptor (GR) antagonists CP-394531 and CP-409069 were examined. The discovery of the potent, selective, nonsteroidal GR antagonist (CP-472555) with anti-GR and anti-obesity activity in animal models is described.

Oriented Peptide Mixture Libraries can provide a full matrix of preferred and disfavored amino acids at each subsite of an optimal substrate for a new proteinase. This approach is rapid and convenient, requiring only two mixture libraries to complete the analysis. In this paper we demonstrate an extension of this type of analysis, using a focused library employing unnatural amino acids to probe the depth of the S1 position in th Read More

Modification of the pendant functionalities on a quinazolinone scaffold led to potent antagonist activity for integrin αVβ3 with selectivity over integrin αIIbβ3. Various guanidine mimetics, linkers, and arylsulfonamides were investigated to optimize the series. A molecular model was constructed based on a published X-ray structure and used to analyze ligand-receptor interactions. We identified key interactions for the Read More

A series of N-benzyl-N-hydroxy-3-(cyclopentyloxy)-4-methoxybenzene carboxamide analogues have been investigated as PDE4 inhibitors. Two compounds, 3- carboxylic (12b) and 3-hydroxamic acid (13b) derivatives, have shown potent inhibition toward PDE4, with IC50s of 0.114 and 0.047 μM, respectively. Docking of the compound 13b into the binding pocket of the PDE4 catalytic domain revealed interactions correspondin Read More

A novel undecylresorcinol dimer (1) was isolated from Coleophoma sp. and inhibited cFMS receptor tyrosine kinase (IC50 of 0.4 μM), with greater than 10-fold selectivity versus nine other protein kinases. The known fungal metabolites balanol and altenusin inhibited cFMS kinase and pp60c-Src kinase, respectively, even more potently and selectively. Altenusin inhibited pp60c-Src with an IC50 of 20 nM and a selectivity of at least Read More

A computer-generated homology model of the antimicrobial target Helicobacter pylori urease was derived, using the x-ray crystal structure of Klebsiella aerogenes as a template, in order to design novel urease inhibitors. Based on these computational studies, several heterocyclic hydroxamic acid derivatives have been designed, synthesized, and examined for their ability to inhibit urease activity.

The synthesis and biochemical evaluation of a series of esters of 4- sulfamoylated cinnamic acid as potential inhibitors of the enzyme estrone sulfatase (ES) is reported. The results of the study show that the esters of trans 4-sulfamoylated cinnamic acid are weaker irreversible inhibitors of ES in comparison to 4- methylcoumarin-7-O-sulfamate (COUMATE) and its tricyclic derivatives such as 667- COUMATE, as well as the ste Read More

Advanced oral squamous carcinoma (OSC) is typically treated with 5- Fluorouracil (5-FU) based regimens. Capecitabine (CAP) is a thymidine phosphorylase (TP) activated oral fluoropyrimidine, rationally designed to generate 5-FU preferentially within tumours. The high activity of CAP in intestinal and breast cancer suggests that CAP may have a role in the therapy of OSC. This tumour selectively is achieved through exploi Read More

Meta-[131I]iodobenzylguanidine ([131I]MIBG), used for neuroblastoma treatment, binds to the noradrenaline transporter (NAT). After NAT gene transfection, other tumour types might be treatable with [131I]MIBG. At 14 MBq, carrier-added [131I]MIBG (1110 MBq / mg) delayed tumour regrowth in NAT gene-transfected xenografts by 39-days, while no-carrier-added [131I]MIBG (>104 GBq / mg) cured 100% of tumours.

Oxidative stress is the main pathophysiological mechanism involved in the development of stroke. Severe DNA damage induced by oxidative stress or apoptotic stimuli activates poly (ADP-ribose) polymerase (PARP), causing a rapid depletion of nuclear NAD pools, cellular energy, and thiols. The biochemical activity of nicotinamide in the body is based on its conversion into NAD. Nicotinamide and its structural analogues possess a Read More

The methanol extract from Salvia miltiorrhiza Bungee showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535 / pSK1002 against the mutagen, Trp-P-1, which requires liver metabolizing enzyme. The methanol extract was successively re-extracted with dichloromethane, butanol, and water. Three suppressive compounds were isolated by SiO2 column chromatography fro Read More

A series of enediyne prodrugs with (E)- or (Z)-3-hydroxy-4-(arylmethylidene)cyclodeca-1,5- diyne scaffolds have been synthesized via an intramolecular Nozaki-Hiyama-Kishi reaction as the key step. Cytotoxicity in micro molar range against P388 cancer cell line was observed for selected compounds and a structure-activity relationship is discussed.

The objective of this study was to investigate functional expression of peptide transporters on the rabbit retina. In vivo and ex vivo retina / choroidal uptake studies were carried out with New Zealand albino rabbits. [3H]Gly-Sar was used as the model peptide transporter substrate. [3H]Gly-Sar solutions, in the presence and absence of specific inhibitors, were added to the vitreal side of the retina. Results indicate that retinal upt Read More

Two nitrogen mustard (N-mustard ) agents were synthesized utilizing ethylene diamine and hexane diamine as the parent compounds. These N-mustard agents were solids at 25o C and stable while stored dry at -10°C. The two N-mustards assumed the configuration of identical twin drugs which when placed in aqueous solution were highly reactive. Both N-mustards were soluble in aqueous NaHCO3 buffer and expressed al Read More

Thiourea analogues of NNC 26-9100 (2) were prepared as somatostatin receptor subtype 4 (sst4) ligands. The indole 9 exhibited high affinity (Ki = 23 nM) and about a 100-fold selectivity at sst4 compared to sst2 receptors. The (imidazol-4-yl) propyl group appears to play a major role in the affinity and selectivity of these thioureas at sst4.

Several types of porous surfaces, including cotton cloth, paper, wood, silk, and wool, have been modified chemically by the attachment of polycationic adjuncts to provide them with antifungal characteristics. Structure / activity relationships for the antifungal adjuncts have been determined in this investigation for the effect on a series of fungi.