Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence
| Autor: | Paul Brennan, Dominique Westbrook, Colleen P. Gibbons, Robin Ward, Carly L. Nichols, Michael R. Sutton, Mark Holbrook, Julian Blagg, Nicholas J. Edmunds, Alison Bridgeland, Tiffini Brabham, Kelly Conlon, Andrews Mark David, Peter J. Bungay, Gavin A. Whitlock, Alan S. Jessiman, Karin McIntosh, James Root, Martin P. Green, Gordon McMurray, R. Ian Storer, Paul V. Fish, Alan Daniel Brown, Giles Hanton, Kerry af Forselles |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
Agonist medicine.medical_specialty medicine.drug_class Clinical Biochemistry Pharmaceutical Science Urinary incontinence Pharmacology Biochemistry Dogs Pharmacokinetics In vivo Internal medicine Drug Discovery medicine Animals Receptor Molecular Biology 5-HT receptor ADME Molecular Structure Chemistry Organic Chemistry Azepines Rats 5-HT2C receptor Disease Models Animal Pyrimidines Urinary Incontinence Endocrinology Molecular Medicine medicine.symptom Serotonin 5-HT2 Receptor Agonists |
| DOI: | 10.1016/j.bmcl.2010.11.120 |
| Popis: | New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2A or 5-HT2B receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|