Focused sample libraries for specific application examples
Inte:Ligand's application scientists have created focused sample libraries for several selected targets and one special reaction, which is available free of charge. The parameter sets for these libraries are shipped with ilib diverse and can easily be modified to create slightly different and/or larger compound libraries.
Library 1: Human rhinovirus coat protein inhibitors
Rhinoviruses belong to the group of picornaviruses and present the most frequent cause for common cold. Antirhinoviral compounds, the so-called human rhinovirus (HRV) coat protein inhibitors, have been developed to bind into a hydrophobic pocket in the viral capsid, stabilizing the capsid and interfering with cell attachment and/or uncoating of the viruses. In this context, the WIN compounds, synthesized by the former Winthrop-Sterling group form an interesting class of inhibitors. One of these compounds, Pleconaril (WIN 63843), is expected to be launched in summer 2004 . More than 100 rhinovirus serotypes are known and can be classified into major group viruses using ICAM-1 as their cellular receptor and in minor group viruses, which use members of the low-density lipoprotein family to attach to cells . In the absence of an inhibitor the hydrophobic binding pocket, which is situated underneath a depression on the virus capsid surface, can be either empty or occupied by a cellular pocket factor, a lipid or fatty acid. This study is targeted on generating libraries of possible new HRV coat protein inhibitors built in an analogous structural manner as the WIN compounds.
Library 2: 4-Aminoquinoline derivatives as NMDA-NR1/2B antagonists
Excessive activation of N-methyl-D-aspartate (NMDA) receptors and resulting calcium overload of neurons is thought to be a key contributor to neuronal cell death following acute cerebral ischaemia. In this context, NMDA receptor antagonists have been demonstrated to be potent neuroprotective agents in animal models of focal cerebral ischemia. Therefore, selective NR1/2B subtype antagonists are considered as potentially attractive drugs for the treatment of neurodegenerative disorders such as stroke, brain trauma, pain, and Parkinson's disease. 
Library 3: Potential inhibitors of Human Coagulation Factor Xa
The prevention of blood coagulation is a major topic considering serious physiological reactions of undesired blood clotting that can lead to myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism. Factor Xa is a trypsin-like serine protease that converts the prothrombin zymogen to its active form thrombin and initiates the final stage of the blood coagulation pathway. Thrombin catalyzes enzymatic reactions that result in the formation of fibrin, the important binding part for blood clotting. Compared to thrombin, factor Xa acts on an earlier level than thrombin. The mechanism of amplification in the blood coagulation cascade causes a small amount of factor Xa to produce a large amount of thrombin. Hence, the direct inhibition factor Xa is considered as more favorable regarding the safety/efficacy ratio compared to other anticoagulants. Other anticoagulant substance classes like vitamin K antagonists or thrombin inhibitors are considered to have a higher bleeding risk than factor Xa inhibitors. Therefore, inhibition of factor Xa has appeared as an attractive target for the development of new anticoagulants. 
Library 4: Protein kinase B inhibitors
PKB plays a key role in cell differentiation, proliferation and tumor genesis. PKB is an anti-apoptotic protein kinase that has elevated activity in a number of human tumors . In this context, PKB inhibitors have been demonstrated to be potent agents against cancer. Therefore, a new group of PKB inhibitors, 'Akstatins' are considered as potentially attractive drugs for the inhibition of PKB.
Library 5: Biginelli condensation
Multicomponent reactions (MCRs), like the Biginelli, Mannich, Passerini, and Ugi reactions, are single-pot reactions of three or more reactants which form products containing portions of all the components. Although some of these protocols have been known for over 100 years, MCRs have recently found new popularity with their implementation in combinatorial and solid-phase synthesis, allowing the generation of large combinatorial libraries in a single step. The Biginelli condensation is a versatile reaction for the generation of substituted dihydropyrimidinones . In this example, we take a recent publication on this topic and translate the chemical reaction into a protocol for ilib diverse. This allows us to reproduce a subset of the products which are accessible from the educts reported in the paper .
|||Viropharma Inc., www.viropharma.com|
|||Kotalar, P.R., Bella, J., Olson, N.H., Baker, T.S., Rossmann, M.G. Structural studies of two rhinovirus serotypes complexed with fragments of their cellular receptor. The EMBO Journal, 1999, 18 (22), 6249-59|
|||Alanine, A. et al. 1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl amines, a Novel Class of NR1/2B Subtype Selective NMDA Receptor Antagonists. Bioorganic & Medicinal Chemistry Letters, 2003, 13, 3155-9|
|||Ostrovsky, D. et al. Analysis of Activity for Factor Xa Inhibitors Based on Monte Carlo Simulations. J. Med. Chem. 2003, 46, 5691-5699.|
|||Reuveni, H. et al., Toward a PKB Inhibitor: Modification of a Selective PKA Inhibitor by Rational Design, Biochemistry, 2002, 41, 10304-10314.|
|||Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.|
|||Stadler A., Kappe C.O. Automated Library Generation Using Sequential Microwave-Assisted Chemistry. Application toward the Biginelli Multicomponent Condensation. J. Comb. Chem. 2001, 3(6), 624-30.|