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

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

  • J Med Chem. 2020 Jul 9;63(13):7369-7391. doi: 10.1021/acs.jmedchem.0c00595.
Claudia Mugnaini 1,  Magdalena Kostrzewa 2 3,  Marta Bryk 3,  Ali Mokhtar Mahmoud 2,  Antonella Brizzi 1,  Stefania Lamponi 1,  Gianluca Giorgi 1,  Francesca Ferlenghi 4,  Federica Vacondio 4,  Paola Maccioni 5,  Giancarlo Colombo 5,  Marco Mor 4,  Katarzyna Starowicz 6,  Vincenzo Di Marzo 2,  Alessia Ligresti 2,  Federico Corelli 1
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 2 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
  • 3 Institute of Genetics and Biophysics, National Research Council of Italy, Via Pietro Castellino 111, 80131 Napoli, Italy.
  • 4 Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
  • 5 Institute of Neuroscience, National Research Council of Italy, S.S. 554, km 4,500, 09042 Monserrato, Cagliari, Italy.
  • 6 Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343 Cracow, Poland.
PMID: 32515588 DOI: 10.1021/acs.jmedchem.0c00595
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).

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