Combinatorial synthesis and screening of heterocyclic druglike scaffold libraries

Most drug molecules clearly fall in the category of non-oligomeric, small-sized, hetero-cyclic molecules. Thus, exploitation of combinatorial technology for drug discovery can be expected to rely heavily on the ability to generate chemical libraries of such molecular entities. Solid-phase synthesis (SPS) makes a scaffold amenable to split-pool protocols, and also offers general advantages such as driving difficult reactions to completion through the employment of excess reagents, and easy...

Deconvolution methods in solidphase synthesis

Dolle (Pharmacopeia Inc., Princeton, NJ, U.S.A.) Mixture libraries and deconvolution 287 Mass spectrometry and structure determination 291 Encoded combinatorial libraries 292 Oligonucleotide encoding strands 292 Molecular tags as an encoding strategy 292 Patent strategies in molecular diversity K. Bozicevic (Fish & Richardson P.C., Menlo Park, CA, U.S.A.) Real and intellectual property 298 Types of intellectual property 299 Combinatorial chemistry alliances in the 1990s...

Synthetic peptide libraries

Arizona Cancer Center, Department of Medicine and Department of Microbiology and Immunology, College of Medicine, The University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, U.S.A. Combinatorial chemistry is a rapidly developing field. It is now considered as one of the most important recent advances in medicinal chemistry. In addition to drug lead identification, combinatorial chemistry can also be applied to the optimization of the initial lead. Most pharmaceutical companies have...

Split and recombine strategy

For linear multistep syntheses, the split and recombine strategy is a fast and effective method of producing large libraries. In fact, a synthesis with x inputs and y chemical steps gives rise to a library ofxy components. Chemical tagging methods have been used extensively for the identification of active components in such libraries 6 . An alternative to chemical tagging is a coding system that uses radio frequency (rf) encodable microchips. Fig. 6. Split synthesis strategy using the OntoCODE...

References

Lett., (1978) 905. Adi96 Adinolfi, M., Barone, G., De Napoli, L., Iadonisi, A. and Piccialli, G., Tetrahedron Lett., 37 (1996) 5007. Aja95 Ajayaghosh, A. and Rajasekharan Pillai, V.N., Tetrahedron Lett., 36 (1995) 777. Aki85 Akiyama, M., Shimizu, K., Aiba, S. and Katoh, H., Bull. Chem. Soc. Jpn., 58 (1985) 1421. Ale92 Alewood, P.F., Brinkworth, R.I., Dancer, R.J., Garnham, B., Jones, A. and Kent, S.B.H., Tetrahedron Lett., 33 (1992) 977. Als94 Alsina, J., Rabanal, F.,...

Spatially dispersed strategy

Automated synthesis of peptide and oligonucleotide libraries was initiated about 10 years ago 4 . Within the last three years, there has been much attention focused on the generation of combinatorial libraries of small molecules. As with biopolymers, the use of solid resin support was central to the advance of this field. In solid-phase synthesis, one of the reactants is covalently bound to the solid support and an excess of the other reac-tants may be used in each step to drive reactions to...

Solidphase organic chemistry SPOC

E1196, Her96, Fru96, Pat96, Ter95b, Gor94, Des94a, Las87, Fre81, Hod80, Lez78b, Cro76, Pat75 The following issues are devoted to combinatorial chemistry and contain some interesting SPOC reviews Acc. Chem. Res., 29 (3) (1996) Chemtracts-Org. Chem., 8 (1) (1995). For a historical perspective, see Merrifield's original paper Mer63. a-Amino phosphonate P-Amino thioester Ammonium salt Aryl alkyne Aryl arsonic acid Aryl bromide Aryl chloride Aryl iodide Aryl selenic acid Aryl sulfonic acid Azide...

HTS assay validation guidelines

All HTS assays should have a solid scientific rationale, e.g., that modulators (agonists, partial agonists, mixed agonists antagonists or pure antagonists) that elicit a particular mechanistically based endpoint will be predictive of clinical utility. While this requirement may seem obvious, it is one of the more complex issues in managing HTS, particularly at larger research-oriented sites. For a company founded on a single technology, such as inhibition or activation of a newly discovered...