Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.

Abstract	The 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).
Authors	Claudia Mugnaini, Magdalena Kostrzewa, Marta Bryk, Ali Mokhtar Mahmoud, Antonella Brizzi, Stefania Lamponi, Gianluca Giorgi, Francesca Ferlenghi, Federica Vacondio, Paola Maccioni, Giancarlo Colombo, Marco Mor, Katarzyna Starowicz, Vincenzo Di Marzo, Alessia Ligresti, Federico Corelli
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 13 Pg. 7369-7391 (07 09 2020) ISSN: 1520-4804 [Electronic] United States
PMID	32515588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	4-Quinolones Anti-Asthmatic Agents Cannabinoid Receptor Agonists Ligands Receptor, Cannabinoid, CB1 Receptor, Cannabinoid, CB2 Colforsin Iodoacetic Acid
Topics	4-Quinolones (chemistry) Animals Anti-Asthmatic Agents (chemistry, pharmacology) CHO Cells Cannabinoid Receptor Agonists (chemical synthesis, pharmacology) Chondrocytes (drug effects, metabolism, pathology) Colforsin (pharmacology) Cricetulus Disease Models, Animal Drug Design Drug Evaluation, Preclinical (methods) Humans Iodoacetic Acid (toxicity) Ligands Male Mice NIH 3T3 Cells Osteoarthritis (chemically induced, drug therapy) Rats, Wistar Receptor, Cannabinoid, CB1 (genetics, metabolism) Receptor, Cannabinoid, CB2 (agonists, antagonists & inhibitors, genetics, metabolism) Structure-Activity Relationship Walking

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