Exploring adamantine-like scaffolds for a wide range of therapeutic targets

Abstract

For over eighty years, adamantane ring has interested organic chemists for its simplicity and symmetry. The rigid tricyclo[3.3.1.13,7]decane skeleton has provided a unique structural template for evaluating important theoretical concepts in chemistry.

The physical and chemical properties of the adamantane nucleus have largely overshadowed the structure’s contribution to the discovery of human therapeutics. Nevertheless its application in medicinal chemistry has become more and more significant in the last decades, where the adamantane ring was identified as a key structural subunit in several synthetic drugs for multiple targets. Adamantane is often considered as providing just the critical lipophilicity readily available as an add-on for known pharmacophoric units. Although its valuable contribution to medicinal sciences, adamantane ring can lead to solubility and stability problems which compromise the pharmacokinetic profile of the potential drug. Hence many research teams have worked out alternatives on adamantyl-based compounds in order to avert these issues, especially by attaching polar groups at key positions.

In the last few years, the research group of Dr. Santiago Vázquez from University of Barcelona has developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. So far, we have synthesized ring-contracted, ring-expanded and oxa analogues of the drugs amantadine, rimantadine and memantine with anti-influenza, NMDA receptor antagonist and trypanocidal activities, proving the capacity of these polycycles to substitute the adamantane ring.

As described previously, the replacement of the adamantane ring with other polycyclic scaffolds can lead to compounds with better pharmacodynamic and pharmacokinetic profiles. In particular, my Ph.D. research has focused mainly on the substitution of the adamantane moiety in inhibitors of different targets.

1) NMDA receptor antagonists: design, synthesis, pharmacological evaluation and electrophysiological studies of new compounds. 2) 11β-HSD1: design, synthesis, pharmacological evaluation and computational studies of new compounds. 3) Soluble epoxide hydrolase inhibitors: design, synthesis, pharmacological evaluation and in vitro cellular studies of new compounds.

From the results of this dissertation, we have confirmed the ability of the new scaffolds to replace the adamantane nucleus with successful outcomes. The work derived from this thesis have been published in peer scientific journals, as well as in two different patent applications.

La recerca duta a terme durant la meva tesi doctoral ha estat centrada principalment en la substitució de l’anell d’adamantà en inhibidors de diferents dianes. Fins al moment, durant la present tesi, he sintetitzat estructures policícliques de diferent mida i forma com anàlegs de l’adamantà per la seva substitució en múltiples dianes farmacològiques. Concretament, he preparat famílies de compostos que tenen com a diana el receptor NMDA del glutamat per la malaltia d’Alzheimer, l’enzim 11β-HSD1 pel tractament de la diabetis mellitus tipus 2 i malalties cardiovasculars, i l’enzim sEH pel tractament del síndrome metabòlic i estats de dolor i inflamació. El nostre objectiu és proporcionar nous compostos amb propietats fisicoquímiques millorades, mentre mantenen la seva potència biològica. Amb la seva avaluació en assajos in vitro, hem demostrat la capacitat d’aquest policicles de substituir l’anell d’adamantà.

Cal destacar que la meva recerca ha inclòs el disseny, la síntesi i la caracterització completa dels compostos finals, així com l’avaluació farmacològica i els assajos in vitro d’una de les famílies de compostos.