Introducing nitrogen atoms to amidoalkylindoles: potent and selective cannabinoid type 2 receptor agonists with improved aqueous solubility.

Previously we identified a series of amidoalkylindoles as potent and selective CB2 partial agonists. In the present study, we report our continuous effort to improve the aqueous solubility by introducing N atoms to the amidoalkylindole framework. Synthesis, characterization, and pharmacology evaluations were described. Bioisosteric replacements of the indole nucleus with an indazole, azaindole and benzimidazole were explored. Benzimidazole 43 (EC50,CB1 = NA, EC50,CB2 = 0.067 µM) and azaindole 24 (EC50,CB1 = NA, EC50,CB2 = 0.048 µM) were found to be potent and selective CB2 receptor partial agonists, both with improved aqueous solubility.

Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors.

Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1.

Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis.

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.