Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: Structure–activity relationships of (thioalkyl)phenoxy benzylamines

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 19; pp. 5303 - 5306
• Main Authors: Middleton, Donald S., Andrews, Mark, Glossop, Paul, Gymer, Geoffrey, Hepworth, David, Jessiman, Alan, Johnson, Patrick S., MacKenny, Malcolm, Stobie, Alan, Tang, Kim, Morgan, Paul, Jones, Barry
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2008; Elsevier
• Subjects: Benzylamines - chemical synthesis; Benzylamines - chemistry; Benzylamines - pharmacology; Biological and medical sciences; Combinatorial Chemistry Techniques; Humans; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phenyl Ethers - chemical synthesis; Phenyl Ethers - chemistry; Phenyl Ethers - pharmacology; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - chemistry; Serotonin Uptake Inhibitors - pharmacology; Serotoninergic system; Site-directed metabolism; SSRI; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Volume of distribution; SSRI; Site-directed metabolism; Volume of distribution; Sulfonamide; Intravenous administration; Rat; Rodentia; Oral administration; Metabolism; In vitro; Organic sulfide; Selective serotonin reuptake inhibitor; In vivo; Vertebrata; Mammalia; Distribution volume; Structure activity relation; Animal; Tertiary amine; Neurotransmitter; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.08.040

A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulphonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile. A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.