Tricyclic Pyrazoles. 4. Synthesis and Biological Evaluation of Analogues of the Robust and Selective CB2 Cannabinoid Ligand 1-(2‘,4‘-Dichlorophenyl)-6-methyl-N-piperidin-1-yl- 1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide

• Published in: Journal of medicinal chemistry Vol. 49; no. 25; pp. 7502 - 7512
• Main Authors: Murineddu, Gabriele, Lazzari, Paolo, Ruiu, Stefania, Sanna, Angela, Loriga, Giovanni, Manca, Ilaria, Falzoi, Matteo, Dessì, Christian, Curzu, Maria M, Chelucci, Giorgio, Pani, Luca, Pinna, Gérard A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2006; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry, Medicinal; HL-60 Cells; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Life Sciences & Biomedicine; Ligands; Medical sciences; Miscellaneous; Mitogen-Activated Protein Kinase 1 - biosynthesis; Mitogen-Activated Protein Kinase 3 - biosynthesis; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Radioligand Assay; Receptor, Cannabinoid, CB2 - agonists; Science & Technology; Structure-Activity Relationship; SR 144528; 2-ARACHIDONOYLGLYCEROL; ACTIVATION; ANTAGONIST; PHARMACOLOGY; INVOLVEMENT; INVERSE AGONIST; MICROGLIAL CELLS; EXPRESSION; RECEPTOR CB2; Human; Promyelocytic leukemia; Ligand; CB2 cannabinoid receptor; Selectivity; Tricyclic compound; In vitro; HL60 cell line; Cell line; Structure activity relation; Piperidine derivatives; Carboxamide; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060920d

New analogues (2a−p) of the previously reported CB2 ligands 6-methyl- and 6-chloro-1-(2‘,4‘-dichlorophenyl)-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides (1a,b) have been synthesized and evaluated for cannabinoid receptor affinity. One example, 1-(2‘,4‘-dichlorophenyl)-6-methyl-N-cyclohexyilamine-1,4-dihydroindeno[1,2-c] pyrazole-3-carboxamide (2a) was shown to have single digit nanomolar affinity for cannabinoid CB2 receptors. Furthermore, compounds 2a and 2b, as well as lead structures 1a,b, were also shown to be agonist in an in vitro model based on human promyelocytic leukemia HL-60 cells.