ABSTRACT
The synthesis of multiple organic compounds in parallel arrays is still perhaps the most powerful approach to drug discovery and optimization in the 21st century, despite the dramatic improvements that have been made in structure-based drug design, virtual screening, and diversity-oriented combinatorial chemistry. Described herein are parallel syntheses of small groups of inhibitors for the tumor growth-promoting human enzymes histone deacetylases, inhibitors of the pro-inammatory mediator human secretory phospholipase A2 group IIa, and inhibitors of the viral enzyme HIV-1 protease. The availability of close structural analogs of bioactive compounds facilitates the development of informative structure-activity relationships that can lead to identication of drug leads and clinical candidates with important and improved pharmacological activities. This chapter
demonstrates how derivatization of some simple l-and d-amino acids through parallel solutionand solid-phase synthesis approaches has enabled us to produce nonpeptidic and peptidomimetic compounds as potent inhibitors of human and viral enzymes, with reasonable cell permeability and/or oral bioavailability and potentially valuable pharmacological properties in vivo.
