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EnglishThe hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
| Autori: | |
| Autori: | Mugnaini, C.; Kostrzewa, M.; Bryk, M.; Mahmoud, A. M.; Brizzi, A.; Lamponi, S.; Giorgi, G.; Ferlenghi, F.; Vacondio, F.; MacCioni, P.; Colombo, G.; Mor, M.; Starowicz, K.; Di Marzo, V.; Ligresti, A.; Corelli, F. |
| Titolo: | Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity in Vivo |
| Numero degli autori: | 16 |
| Data di pubblicazione: | 2020 |
| Rivista: | JOURNAL OF MEDICINAL CHEMISTRY |
| Codice identificativo ISI: | WOS:000550753700047 |
| Codice identificativo Scopus: | 2-s2.0-85088210361 |
| Volume: | 63 |
| Fascicolo: | 13 |
| Pagina iniziale: | 7369 |
| Pagina finale: | 7391 |
| Numero di pagine: | 23 |
| Lingua: | Inglese |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1021/acs.jmedchem.0c00595 |
| Parole Chiave: | 4-Quinolones; Animals; Anti-Asthmatic Agents; CHO Cells; Cannabinoid Receptor Agonists; Chondrocytes; Colforsin; Cricetulus; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Iodoacetic Acid; Ligands; Male; Mice; NIH 3T3 Cells; Osteoarthritis; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; Walking |
| Data di presentazione: | 2021-04-07T11:58:11Z |
| Appare nelle tipologie: | 1.1 Articolo su rivista |
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