Rapid combinatorial access to a library of 1,5-disubstituted-3-indole-N-alkylacetamides as CB2 receptor ligands

In our research program on new cannabinoid receptor modulators,9-11 we decided to investigate the possibility to identify novel CB2 ligands starting from commercially available 5-hydroxyindole-3-acetic acid (Figure 2). This scaffold offers three points (COOH, OH, NH groups) to enhance chemical diversity through chemical manipulations in an easy, rapid, and profitable way. In particular, we envisioned the possibility to generate a small library of compounds by converting the carboxylic acid functionality into a secondary or tertiary amide group and performing selective alkylation reactions of the OH and NH moieties using benzyl or allyl halides.