Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT 7/2 inhibitors leading to the identification of a clinical candidate

• Published in: Bioorganic & medicinal chemistry letters 2021-01, Vol.31, p.127669
• Main Authors: Dvorak, Curt A, Rudolph, Dale A, Nepomuceno, Diane, Dvorak, Lisa, Lord, Brian, Fraser, Ian, Bonaventure, Pascal, Lovenberg, Timothy, Carruthers, Nicholas I
• Format: Article
• Language: English
• ISSN: 1464-3405

We report here the synthesis and characterization of a dual 5-HT / 5-HT receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT and 5-HT receptor ligand having a pK  = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT and as an inverse agonist in an in vitro functional assay for 5-HT . In a validated in vivo model for central 5-HT activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED  = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED  = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT receptor binding sites in the frontal cortex of the rat brain with an ED in good agreement with the ED value for central functional effect mediated by 5-HT receptor (ED  = 0.8 mg/kg, p.o., 1 h).