ISOXAZOLES IN MEDICINAL CHEMISTRY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The term privileged structure refers to certain molecular scaffolds that appear to be capable of binding to multiple receptor targets, and consequently with appropriate structure modifications, could exhibit multiple activities. The isoxazole ring plays several roles in medicinal chemistry: prodrug, bioisostere, spacer, and several examples of isoxazole containing drugs are in general medical practice. We are developing synthetic methodology to apply the isoxazole scaffold to significant problems in medicinal chemistry. Our most encouraging progress in our hypothesis-driven Structure-based drug design has been made in (1) neurotransmitter analogs for the treatment for neurological disorders, (2) the SAR of Anti-hypertensive calcium channel antagonists of the nifedipine class, and (3) anti-cancer agents that target G-4 DNA conformation in the c-myc oncogene. Isoxazoles provide conformational restriction in the case of AMPA¿ (Amino Methyl isoxazole Propionic Acid) and its analogs, which are glutamate receptor ligands which have proved important in defining sub-type specificity of this important neurotransmitter. We have developed what we believe to be the first catalytic asymmetric synthesis of AMPA analogs, and have discovered an SAR (Structure Activity Relationship)¿ distinction between the GluR2 receptor and System XC- transporter.¿ The isoxazole serves a function as a bioisostere in our studies of 4-isoxazolyl-1,4-dihydropyridine¿ (ID) calcium channel blockers, wherein we have observed both robust calcium channel activity (single digit nanomolar), as well as a pronounced enantioselectivity of action. We have uncovered a unique SAR for the IDs, and have developed a drug-receptor model as a working hypothesis. Our most recent synthetic studies have focused on the covalent attachment of fluorophores to the ID scaffold, to study the structural dynamics of the calcium channel.¿ A new class of compounds developed in our lab, exemplified by NCS 694332, use the isoxazole as a linchpin to both connect DNA interactive groups and arrange them in a precise conformation in three dimensions. NSC 694332 was found to exhibit single digit micromolar inhibition of a dozen tumor cell lines in the National Cancer Institute's (NCI) screening protocol, and selected by the NCI's Biological Evaluation Committee for in vivo screening. We have developed a working hypothesis that G-4 DNA represents the molecular target, and have obtained evidence supporting that hypothesis. We are applying¿synthetic methodology in our labs to other drug discovery endeavors, and have made preliminary progress in the Type 2 diabetes and infectious disease arenas.¿