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Overview of Rare and Unique Substructure® Classes
Overview of "Rule of Three" Building Blocks
Overview of Cheminformatic Gap Fillers
Overview of Atom Scanning Tools for Highly Focused Libraries
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Synthetic Chemistry from Focus Synthesis Synthons
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Knowledge-Enabling Building Blocks
Focus Synthesis is a new research chemical supplier that uses rational principles based in chemoinformatics in the design of chemical building blocks that are ideally suited for DOS (diversity-oriented synthesis). Focus Synthesis products include members of unique and underrepresented substructure classes, building blocks designed for thorough property space coverage, and precursors for highly focused combinatorial libraries. The mission of Focus Synthesis is to provide tool sets for discovering the drugs of the future by optimizing diversity and enabling comprehensive single-site and isosteric changes in biologically active small molecules that result in optimal SAR knowledge.
Focus Synthesis offers synthons, building blocks, and research chemicals that are optimized for drug discovery using chemoinformatics-based design. In addition to being a research chemical supplier specializing in drug candidate intermediates and other organic chemicals, Focus Synthesis also provides custom synthesis outsourcing, in-house custom chemistry, and proprietary design services.
Many of the building blocks in the Focus Synthesis catalog belong to substructure classes that are rare or unavailable in other chemical catalogs. The underrepresented substructures in these synthons make them ideal for the development of non-obvious variations on current lead molecules, thereby strengthening intellectual property positions. In addition, these distinctive building blocks are excellent tools for improving diversity and property space coverage. Click here to see an online catalog of building blocks with rare and unique substructures®.
Some of these distinctive Focus Synthesis catalog items are depicted below, with the rare substructure components highlighted in red:
Focus Synthesis has also developed subsets of the Rare and Unique Substructure® Classes that are even more distinctive and unusual.
For RubyScaffoldsTM the rare substructure is a monocyclic or polycyclic heterocycle without appended atoms. These exotic heterocycles can help you to explore new areas of chemical structure space. They can also help to enhance your IP position because few if any derivatives are commercially available and most test molecules that you make from them will be distinctive and patentable.
Click here to see an online catalog of RubyScaffoldTM building blocks. Examples of 4 RubyScaffoldsTM currently in stock are shown here, with the rare heterocyclic substructure highlighted red:
For RubyShapesTM, the substructure is rare or unique in commercial catalogs for all possible heavy atom substitutions. In other words, the substructure is a graph consisting of "wild card" atoms and bonds. As building blocks, RubyShapesTM are ideal for improving the diversity of molecular shapes in your corporate collection. The following figure depicts 4 RubyShapesTM molecular structures from the Focus catalog, alongside their rare substructure shapes (substructures highlighted in green):
RubySynthonsTM are ultra-rare molecules for which no examples with the substructure are found in 3 large databases of organic molecules. In addition to the ACD (MDL information systems) and ChemACX (CambridgeSoft) databases of commercial compounds, the RubySynthonsTM contain substructures that are not found in the Emolecules database (>5.3 million organic structures from the literature and commercial sources). The total size of the 3 combined databases is more than 10 times the size of the ACD and ChemACX together. RubySynthonsTM are ideal as starting points for improving the overall diversity of your corporate compound collections and for helping you create highly novel, patentable leads. Examples of RubySynthonsTM are shown below, with rare substructures highlighted in blue:
Focus Synthesis has introduced Cheminformatic Gap Fillers in order to provide druggable building blocks that significantly improve the diversity of commercially available building blocks. One approach to measuring chemical diversity involves determining how evenly distributed a set of molecules are in chemical property space, where the dimensions of the space can be physical properties, chemical properties, topological or geometric parameters based on structure, etc. Useful descriptors for this type of cheminformatic analysis include chemical properties, physical properties, and structure based parameters, and various combinations thereof that can be independently increased or decreased in a straightforward, intuitive manner using structural changes. Polar Surface Area (FISA, area in angstroms of O and N atoms) and Weakly Polar Surface Area (WPSA, area in angstroms of F, Cl, Br, I, S, and P) were chosen here because of their relationship to drug bioavailability in mammals (Wessel et al, 1998; Votano et al, 2004). In the example given here, the parameters were determined using QikProp software from Schrodinger. In the scatter plot shown in the example below, many gaps are evident in the distribution of commercial bromopyridines (ACD) because many of these compounds share similar properties and cluster together. The Focus Gap Fillers have been designed to occupy the gaps, so that their FISA and WPSA values differ by at least 10 angstom squared units from any bromopyridine available from another vendor. Inclusion of Focus Gap Filler building blocks will therefore significantly enhance the diversity of combinatorial libraries derived from bromoarenes.
Click here to view structures, prices and availability for Cheminformatic Gap Filler building blocks.
References for cheminformatic gap fillers:
ACD: abbreviation for Available Chemicals Directory (a product of MDL Information Systems).
Wessel MD, Jurs PC, Tolan JW, Muskal SM,
J Chem Inf Comput Sci. 1998 V38(4): pp726-35
Votano JR, Parham M, Hall LH, Kier LB.
Mol Divers. 2004 V8: pp379-91
Recently, a set of rules has been developed to help identify small molecules suited for the fragment-based lead discovery. This novel approach to drug discovery involves screening libraries of low-molecular weight fragments for their ability to interact with a macromolecular target through protein x-ray crystallography or NMR. Congreve, Carr, Murray and Jhoti determined that small molecules that obey the "Rule of Three" are most suited to this approach: FW < 300, hydrogen bond donors <=3, hydrogen bond acceptors <=3, ClogP <=3.
Focus Synthesis offers a set of over 150 building blocks that meet the basic Rule of Three criteria. More than 80% of these are predicted to be stable in physiological buffers, and could be used directly as screening compounds particularly suited for fragment-based lead discovery. 100% of the "Rule of Three" products are particularly well suited as precursors for lead-like and drug-like molecules.
Click here to view structures, prices and availability for "Rule of Three" building blocks.
References for "Rule of Three":
M. Congreve, R. Carr, C. Murray and H. Jhoti, Drug Discovery Today V8 pp 876-877 (2003)
Many of the synthons and building blocks offered by Focus Synthesis are so unusual that their synthetic chemistry as precursors is not common knowledge. Beginning with isothiazole (FS000701), this section will briefly review synthetic chemistry using a chemical structure schematic with literature references. Where applicable, biological activity will be tabulated for selected end-products formed from Focus Synthesis precursors. These schematics are not meant to be at all comprehensive, but will provide a representative sample of the organic and medicinal chemistry publications for products formed from Focus Synthesis building blocks.
The chemistry of isothiazole (FS000701) is reviewed in the schematic below. Click here to see current pricing and availability for isothiazole.
Focus Synthesis offers sets of isomeric building blocks that differ from one another in the placement of a single methyl group or fluorine atom. For example, the following are currently included in the catalog as Special Order compounds useful as precursors for a methyl scan sublibrary:
Pharmaceutical lead sets made from these building blocks can be used to carry out a comprehensive "methyl scan", determining the effects of methyl group placement on biological activity. The methyl scan technique is a very systematic, rational way of improving the understanding of SAR, while providing a starting point for further modifications to improve selectivity, ADMET characteristics, and potency.
Selected literature references concerning the use of methyl scans in SAR elucidation and design of bioactive molecules:
Pirrung MC et al.
J. Amer. Chem. Soc. V127 pp 4609-4624 (2005)
Rajeswaran WG, Hocart SJ, Murphy WA, Taylor JE, Coy DH.
J Med Chem. 2001 Apr 26; V44 (9): pp 1416-1421.
Slon-Usakiewicz JJ, Sivaraman J, Li Y, Cygler M, Konishi Y.
Biochemistry. 2000 Mar 7; V39 (9): pp 2384-2391.
| *Note concerning Special Order chemicals: these are made to order in 1 to 8 weeks. The minimum order size is 1, 5, or 20 grams. Prices are listed in the catalog for available quantities only. Discounts will often apply to first time orders of Special Order chemicals: please inquire. |
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