Introduction

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.

Technical features

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.

Possible Applications

• 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.

Advantages

• 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.