Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors

Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anti-cancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2), or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), Nacylethanolamine acid amidase (NAAA), or cyclooxygenase-2 (COX-2). Over the last decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their anti-nociceptive and anti-inflammatory effects, as well as protecting the nervous system

Development of novel oxazolo[5,4- d ]pyrimidines as competitive CB 2 neutral antagonists based on scaffold hopping

A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB1/CB2 cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB2 ligands with Ki values less than 1 μM. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB2 binding affinity in the nanomolar range and significant selectivity over CB1 receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29

Synthesis and biological evaluation of ferrocene-based cannabinoid receptor 2 ligands

Ferrocene analogues of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bioorganometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on FAAH. None had any FAAH activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole- 3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM)

Synthesis of bioorganometallic nanomolar-potent CB2agonists containing a ferrocene unit

A small library of ferrocene-containing amides has been synthesized using standard amide coupling chemistry with ferrocenylamine. Ferrocene analogues of known bioactive adamantylamides were shown to be effective cannabinoid receptor (CB1 and CB2) agonists, displaying, in many cases, single-digit nanomolar potency. Three final ferrocene-containing derivatives have been characterized in the solid state by X-ray crystallography and display intramolecular hydrogen bonding of the type NH---C═O. N-Methylation of the amide, confirmed by X-ray crystallography, leads to both loss of hydrogen bonding and biological activity

Du cannabis aux agonistes sélectifs du récepteur CB

Utilisée à l’origine en Asie pour traiter douleurs, spasmes, nausées et insomnies, la marijuana est le psychotrope le plus consommé au monde. L’intérêt du cannabis médical a été reconsidéré depuis peu, menant à de nombreuses recherches et à la commercialisation de médicaments. Les cannabinoïdes naturels et synthétiques exercent des effets bénéfiques dans de nombreuses maladies. Ils sont toutefois accompagnés d’effets indésirables psychiatriques et cognitifs présumés liés au récepteur CB1. Les recherches actuelles tendent à concevoir des molécules thérapeutiques agonistes CB2 sans effets secondaires centraux psychotropes

A rapid route for the preparation of pyrimido[5,4-d]- and pyrido[3,2-d]oxazole

Starting from a 5-amino-2-phenyloxazole-4-carbonitrile building block 3, obtained by reaction of benzoyl chloride (1) and aminomalononitrile p-toluenesulfonate (2), a large range of molecules were synthesized in one or two steps. A total of seven pyrimido[5,4-d]oxazoles 5(a–d)–8 and four pyrido[3,2-d]oxazoles 9–12 have been synthesized. Moreover, synthetic procedures have been adapted to overcome the instability of the oxazole ring

One- or Two-Step Synthesis of C‑8 and N‑9 Substituted Purines

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles <b>1</b>–<b>8</b> in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1<i>H</i>-purin-6-ones <b>9</b>–<b>14</b>, 6-amino-8,9-disubstituted-3,9-dihydro-2<i>H</i>-purin-2-ones <b>15</b>–<b>20</b>, 8,9-disubstituted-3,9-dihydro-2<i>H</i>-purin-2,6-diamines <b>21</b>–<b>24</b> and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1<i>H</i>-purin-2-(3<i>H</i>)-ones <b>25</b>–<b>26</b> were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9<i>H</i>-purin-6-amines <b>27</b>–<b>31</b> and 6-imino-8,9-disubstituted-6,9-dihydro-1<i>H</i>-purin-1-amines <b>32</b>–<b>33</b> were obtained in two steps using formamide and hydrazine, respectively

Benzo[d]thiazol-2(3H)-ones as new potent selective CB2 agonists with anti-inflammatory properties.

International audienceThe high distribution of CB receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: selective CB agonists are able to modulate inflammation without triggering psychotropic effects. In this work, we report a new series of selective CB agonists based on a benzo[d]thiazol-2(3H)-one scaffold. This drug design project led to the discovery of compound 9, as a very potent CB agonist (K = 13.5 nM) with a good selectivity versus CB. This compound showed no cytotoxicity, acceptable ADME-Tox parameters and demonstrates the ability to counteract colon inflammatory process in vivo

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties