INDAZOLE DERIVATIVES AS MODULATORS OF THE CANNABINOID SYSTEM
The present invention refers to the chemical field, in particular to indazole derivatives as modulators of the cannabinoid system. In particular it deals with new compounds obtained by linking a Lonidamine scaffold to amino acids showing a broad range of cannabinoid activities such as affinity for CB receptors, stimulation of G-proteins, selectivity for different CB receptors which are useful in the treatment of pain, obesity, eating diseases, nausea, cancer and avoiding the side effects in AIDS patients.
Compounds (LONI 1-9) were synthesized in good to excellent yields by standard solution phase peptide synthesis (SPPS) via EDC/HOBt-mediated condensation in the presence of NMM as base, using Boc strategy following well-established procedures; N-Boc deprotection was carried out by trifluoroacetic acid treatment. Our novel compounds have high CB1 receptor affinity and selectivity with different biological activity depending on the C-terminal substitution and amino acid residues; given their close structural similarity with rimonabant, we hypothesized a similar biological activity in vivo in the feeding behavior modulation. It was found that compounds containing the C-terminal methyl ester of tert-Leu (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate and Val as the free acid are able to decrease food intake at 10 mg/Kg, acting as inverse agonists/antagonists at the CB1. Thus, it has been supposed that the C-terminal methyl ester group could be easily cleavable in vivo to give the free C-terminal acid derivative.
- Compounds with agonist activity could be involved in the treatment of pain;
- Agonists could potentially act as an anorectic and anti-obesity drug;
- Lonidamine-based compounds with antagonist activity could be used to treat chemotherapy-related nausea and vomiting;
- They can be use to treat loss of appetite and weight in AIDS patients.
- Wide range of binding to CB receptors from subnanomolar (Ki = 0.08 nM) to low nanomolar (Ki = 88 nM) affinity;
- Large spectra of biological activities, spanning from agonists to antagonists of CB receptors.