Design and optimization of selective serotonin re-uptake inhibitors with high synthetic accessibility Part 1

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 8, 2009, Pages 2329-2332

  Andrews, Mark ^a   Brown, Alan ^a   Chiva, Jean Yves ^a   Fradet, David ^a   Gordon, David ^a   Lansdell, Mark ^a   MacKenny, Malcolm ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Re uptake; Seretonin; Transporter

Indexed keywords

FLUOXETINE; LITOXETINE; PAROXETINE; SEROTONIN UPTAKE INHIBITOR; SERTRALINE;

ARTICLE; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; REACTION OPTIMIZATION;

CELL LINE; DRUG DESIGN; HUMANS; PIPERIDINES; SEROTONIN UPTAKE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 63149107635     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.054     Document Type: Article

References (12)

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2. For more background on this short Tmax based approach see:. Middleton D.S., Andrews M.D., Glossop P., Gymer G., Hepworth D., Jessiman A., Johnson P.J., MacKenny M., Stobie A., Tang K., Morgan P., and Jones B. Bioorg. Med. Chem. Lett. 18 (2008) 5303 and the references therein
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4. The perceived high degree of synthetic accessibility of pyrrolidine containing targets was based upon the (wide) range of commercially available, suitably protected, homochiral 3-substituted pyrrolidines.
5. 3H-radiolabelled dofetilide to human hERG Potassium channels expressed in HEK-293 cells.
6. For a review of IKr (hERG) affinity and the issues that it presents in small molecule drug discovery, see:. Jamieson C., Moir E.M., Rankovic Z., and Wishart G. J. Med. Chem. 49 (2006) 5029
7. In-house experience suggested that, for certain SRI series, IKr affinity can represent a significant issue. We were therefore keen to identify at an early stage whether or not this issue was likely to arise in any newly identified lead series.
8. 3H-granisetron to human 5-HT3 receptors expressed in HEK-293 cells.
9. In fact, the synthesis of 33, straightforward as it was, represents, by some way, the most complex synthesis (in terms of total steps) carried out during the course of the work described in this Letter, where our focus was very much on accessing new templates which had a high degree of synthetic accessibility.
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11. See, for example:. Inaba T., Umezawa I., Yuasa M., Inoue T., Mihashi S., Itokawa H., and Ogura K. J. Org. Chem. 52 (1987) 2958
12. Our subsequent efforts in this area will be disclosed in due course.