Letters in Drug Design & Discovery - Volume 3, Issue 5, 2006

In order to help meet the multiple challenges that face today's pharmaceutical industry, scientific institutions would be wise to implement quality systems into their research culture so as to help ensure future success and indeed survival. We describe here how this may be achieved in a straightforward and pragmatic manner without stifling scientific innovation. The multiple benefits of implementing this novel undertaking in a pure research environment are highlighted.

The evolution of a novel class of pyrazinone direct thrombin inhibitors (DTIs) is described. In an effort to improve the solubility and thereby the drug-like properties of pyrazinones that possess non-basic P1 residues, a novel amino P1-P2 linker has been designed from X-ray thrombin-inhibitor complexes. Biochemical evaluation demonstrated that nanomolar binding affinity was attained, and X-ray co-crystal structures reveal an unprecedented binding mode that involves an interaction of the new amino linker with Glu192 of the active site of thrombin. A family of soluble pyrazinones has thereby emerged.

Comparison of binding interactions of a bacterial Glu transporter homologue and the extracellular binding domain of metabotropic Glu receptor subtype (mGlu1) showed Glu adopting bent and extended conformations in Glu transporter and mGlu1, respectively.

The preparation and evaluation of a novel class of CB2 benzimidazole inverse agonists are reported. They showed binding affinities up to 0.7 nM towards CB2 with overall good selectivity over the CB1 receptor. They also reversed the effect of the cannabinoid agonist WIN55212-2 in competition assays showing Ki' values up to 1.2 nM.

A series of novel curcumin analogues were synthesized and bioevaluated for anti-neoplastic activity. These compounds are 2-tetralone-based unsymmetrical α, β-unsaturated ketones with extended conjugation. The majority of the analogues were found to show moderate anti-cancer activity in in-vitro test systems against representative murine and human cancer cell lines. Evidence was obtained that these compounds display cytostatic activity against certain malignant cells and were well tolerated in mice. This study has also revealed various directions whereby the project may be augmented in the future with a view to finding compounds with increased cytotoxicity to neoplastic cells.

A series of piperazinephen-1-ylehtylamines were synthesized and evaluated for their biological activity at the human melanocortin-4 receptor. This modification reduced the size and flexibility of the N-alkyl side-chain of some earlier lead compounds, while maintained the low nanomolar binding affinity.

The anticancer (cytotoxicity against human mammary gland adenocarcinoma cells) and antiinflammatory properties (COX-2 inhibition) of the hydroxycinnamic derivatives trans-3-(3,4,5- trihydroxyphenyl)-2-propenoic acid, trans-ethyl(3,4,5-trihydroxyphenyl)-2-propenoate and diethyl 2-(3,4,5- trihydroxy-phenylmethylene)malonate were screened. Data point out a putative correlation between antiinflammatory and anticancer properties and suggest hydroxycinnamic derivatives as promising lead compounds for the development of anti-inflammatory/chemopreventive agents.

Lamotrigine (LTG) is a modern, effective and well-tolerated antiepileptic drug (AED) with an expected low teratogenic potential and therefore regarded as a relative safe drug for women of reproductive age. Recent studies, however, have demonstrated that co-administration of LTG and combined oral contraceptives (OC's) and pregnancy interfere with the metabolism of LTG with the risk of therapeutic failure. It is therefore recommended that plasma level of LTG should be closely monitored before and after introduction or discontinuation of OC's and monthly during pregnancy.

We have carried out an in vitro study of the growth inhibitory capacity of the neurokinin-1 receptor antagonist L-733,060 at concentrations ranging from 5μM to 40μM against the human pancreas adenocarcinoma CAPAN-1 and PA-TU 8902 cell lines. We also studied the mitogenic action of substance P on both cancer cell lines. A Coulter counter was used to determine viable cell numbers, followed by application of the MTS colorimetric method to evaluate cell viability in these cytotoxicity assays. Nanomolar concentrations of substance P increased the growth of both cell lines and micromolar concentrations of L-733,060 inhibited the growth of the CAPAN-1 and PA-TU 8902 cell lines studied in a dose-dependent manner. The IC50 values were 20.02μM for CAPAN-1 and 18.11μM for PA-TU 8902. In order to demonstrate the presence of neurokinin- 1 receptors in these cancer cell lines, an immunoblot analysis was used. Four bands of 34, 46, 58 and 75 kDa were observed in both cell lines. These new findings suggest that the neurokinin-1 receptor is a new target and that the neurokinin-1 receptor antagonist L-733,060 could be a promising therapeutic drug for the treatment of human pancreas adenocarcinoma.

Functionalisation of an L-RNA oligonucleotide with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''- tetraacetic acid (DOTA) was performed using the N-succinimide ester 2. The DOTA-functionalised L-RNA oligonucleotide 3 was radiolabelled with the positron-emitting radiometals 86Y(III) and 68Ga(III) in radiochemical yields of 76% and 93%, respectively. Compound 4a represents the first example of an oligonucleotide labelled with the positron emitter 86 Y. Biodistribution studies of the 86Y-radiolabelled L-RNA oligonucleotide 4a were performed in Wistar rats showing higher levels of radioactivity in the adrenal glands and kidneys. The low bone uptake (0.19%ID/g after 60 min) is indicative of the high kinetic stability of the 86Y-DOTA chelate in vivo.

Simple amino acid prodrugs of cysteamine and cystamine were synthesized to overcome the problems of palatability and gastrointestinal irritation, while γ-glutamyl prodrugs were synthesized to target the parent drug to γ-glutamyl transpeptidase (GGT). Preliminary cystine-depleting evaluation in vitro suggests further investigation is warranted. Low toxicity of the prodrugs was observed.

N-Hydroxyamide, alkanoloamides, dialkylamino-alkylamides and some of morpholinealkylamides of pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids were prepared and preliminary tested for their cardiovascular activity. Some of the tested compounds presented effects on arrhythmia parameters and blood pressure. The most interesting were dialkylamino-alkylamides and their morpholine analogs (4a-10a), which protected the heart against the bradycardia and diminished mortality of animals. In comparison to the chinidini sulfas the strongest activity was observed for diethylaminoethylamide of pyrimidin-8-on[2,1- f]theophylline-9-acetic acid (4a). Amides (1-3) without the basic center in the substituent showed weak antihypertensive properties.

In the last years scientific interest in homocysteine is growing. Homocysteine is a risk factor for cardiovascular morbidity and mortality in the general population with normal renal function. The relationship between homocysteine and cardiovascular disease in patients with renal failure is unclear. This review shows up homocysteine metabolism and its interactions with drugs and diseases, summarizes homocysteine's toxic effects and the results of clinical studies about the effects of homocysteine-lowering therapy on hard endpoints like cardiovascular morbidity and mortality, and describes which kind of treatment can reduce homocysteine in dialysis patients.

In the article entitled "Pyrazinobenzodiazepines as Potent Nonpeptide Vasopressin Receptor Antagonists" by Jay M. Matthews et al. (Letters in Drug Design & Discovery, 2005, Vol. 2(3), 219-223) the authors report that for the Page 222, column 1, paragraph 3, line 9: The reduction of urine osmolality should be 77% (not 23%). Page 222, column 2, line 3: The alteration of urine osmolality should be -81% (not -19%).