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 review articles rapidly. “Letters in Drug Design & Discovery” is thus being launched to meet this need. Letters in Drug Design & Discovery publishes original letters on all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly and take full advantage of internet technology for both the submission and review of manuscripts. The journal is essential reading to all pharmaceutical scientists involved in research in drug design and discovery. There will be four issues of this journal published in 2004. The publication frequency of the journal will increase gradually in the years to come. The internationally eminent editorial board including such eminent authorities as S.S. Abdel-Meguid, J.D. Adams, S. Ahmed, J. Baranowska-Kortylewicz, E.J. Barreiro, D.B. Berkowitz, P.R. Bernstein, R.F. Borne, T. Burke, F.P. Bymaster, F.I. Carroll, B.K. Cassels, C.H. Chen, P.A. Cole, J. Conn, M. Crider, W.-M. Dai, D.R. Davis, J.W. Ellingboe, D.K. Ferris, H.C. Fibiger, A.J. Fischman, D. Flynn, K.R. Fox, F.K. Friedman, E.P. Garvey, M.A. Geyer, D.S. Goodsell, S. Guccione, A. Harvey, F.F. Hefti, K. Herscheid, J.F. Honek, H.N. Jayaram, A.Y. Jeng, M. Kahn, M. Kassiou, T.H. Koch, H.-Y. Koh, H. Kubinyi, Y. Kurogi, E.J. LaVoie, P.Y. Lam, J. Lee, H. LeVine, A.J. Lewis, B.T. Liang, G.K. Lloyd, T. Loftsson, K. Maiese, R. Mairs, A. Makriyannis, J.E. Manson, B.E. Maryanoff, R.P. Mason, S. Mobashery, J.J. Nestor, J.L. Neumeyer, P.A. Newhouse, A.H. Newman, F.G. Njoroge, D.A. Nugiel, I. Ojima, Y. Okada, D.F. Ortwine, J. Pearlman, L.M. Pelus, E. Pop, J.E. Rice, K.C. Rice, P.D. Roepe, A.W. Root, D.P. Rotella, T.K. Sawyer, R.B. Silverman, N.E. Sladek, D.S. Soriano, E.B. De Souza, R.E. Tanzi, H.F. VanBrocklin, B. Wang, D.J. Waxman, C.D. Wegner, R.L. White, J.S. Williamson, Y. Yamamoto, L.Yang, Z.-J. Yao and R. Zhang will undoubtedly guide me in the editorial responsibilities and ensure the very highest standards. The opinions expressed by six Nobel Laureates can be reviewed at www.bentham.org / nobel which reflect the excellent reputation that Bentham Science Publishers enjoy. I keenly look forward to the wide acceptance of this new journal by the community of scientists working in the field of drug design and medicinal chemistry.

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 the catalytic site of the alpha secretase ADAM-10. This analysis indicates that ADAM- 10 will accept amino acids with substantial length and hydrophobicity (e.g. 2- naphthylalanine), but suggests that the S1 site has limitations in the apparent “width” of substituents being presented (e.g. 1-naphthylalanine; gamma branching). A highly selective and efficient substrate for ADAM-10, with a selectivity factor of 380,000 M-1 s-1, was derived from the predicted consensus substrate. This detailed analysis provides a starting point for the design of inhibitors of this interesting proteinase.

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 quinazolinone and arylsulfonamide groups that may explain the changes in potency in the structure-function study.

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 corresponding to those of the cAMP substrate.

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 400-fold versus nine other protein kinases. Balanol inhibited cFMS receptor kinase with an IC50 of 1 nM and selectivities of 14-75-fold versus pp60c-Src and VEGF receptor kinases and greater than 10,000-fold versus seven other kinases.

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 steroidal inhibitor estrone-3-O-sulfamate (EMATE). Structureactivity relationship determination indicates that the flexible nature of the cinnamic acid backbone results in these compounds possessing greatly reduced inhibitory activity compared to the corresponding coumarin derivative. Furthermore, from the superimpositioning of the synthesised compounds onto the substrate, we propose that steric hindrance is an important factor which results in a marked decrease in the inhibitory activity within the large alkyl chain containing compounds.

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 exploitation of the significantly higher activity of TP in tumour compared with healthy tissue. In the present study, the epithelial and macrophages TP expression were significantly higher in OSC than in non-dysplastic oral leukoplakia (NDOLP) (p=0.004, p=0.005; respectively). Because OSC is sensitive to 5-FU, and TP expression is significantly higher in OSC than in NDOLP, TP-activated CAP could be a promising therapy worthy of clinical investigation.

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 weak inhibitory effect on PARP. Nicotinamide exerts its neuroprotective effects by increasing NAD synthesis and ATP production indirectly and inhibiting PARP directly. By inhibiting PARP, membrane phosphatidylserine exposure and DNA fragmentation, nicotinamide can prevent brain necrosis and apoptosis effectively. Administration of nicotinamide at an early stage of stroke provides a new means to rescue the still viable but injured nerve cells within the ischemic and limit areas.

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 from dichloromethane fraction and identified as tanshinone IIA (1), tanshinone I (2) and Cryptotanshinone (3) by GC, GC-MS, 1H- and 13C-NMR spectroscopy. Compounds 1, 2 and 3 inhibited the SOS-inducing activity of Trp-P-1 in the umu test. Gene expression was suppressed by 76%, 96% and 81% at less than 0.18 μmol / mL, 9 respectively. The ID50 (50% inhibition dose) values were 0.03 μmol / mL 0.008 μmol / mL and 0.010 μmol / mol, respectively. These compounds were assayed with activated Trp-P-1. Compound 2 showed suppressive effect of SOS-inducing activity of activated Trp-P-1 but compounds 1 and 3 did not.

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 uptake of [3H]Gly-Sar was significantly inhibited in the presence of other known peptide transporter substrates, such as Gly-Pro and cephalexin. Importantly, valganciclovir, a peptidomimetic prodrug of ganciclovir, also inhibited uptake of [3H]Gly-Sar. These studies therefore, indicate that peptide transporters are functionally expressed on the rabbit retina and retinal concentrations of GCV may be enhanced by targeting these transporters through prodrug derivatization.

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 alkylation activity directed towards a nucleophilic primary amine target (4-chloroaniline) at blood pH 7.4 and 37°C. Utilizing the fluorescent probe fluorescamine, which is highly specific for primary amines, the quantity of unreacted nucleophilic 4-chloroaniline remaining after a known time period was determined. This enabled the calculation of rate constants and the determination of rate equation for alkylation to be first-order for N,N,N',N'-tetrakis(2-chloroethyl)ethane-1,2-diamine and zero-order for N,N,N',N'- tetrakis(2-chloroethyl)hexane-1,6-diamine. Molecular property descriptors such as Log P, parachor, molar volume, molar refractivity, dipole, molecular volume & area, and polar surface area were calculated for comparison. Zero violations of the Rule of 5 indicates these two mustard agents will have good bioavailability and good bioactivity.

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.