Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists

John M Fevig; Jianxin Feng; Karen A Rossi; Keith J Miller; Ginger Wu; Chen-Pin Hung; Thao Ung; Sarah E Malmstrom; Ge Zhang; William J Keim; Mary Jane Cullen; Kenneth W Rohrbach; Qinling Qu; Jinping Gan; Mary Ann Pelleymounter; Jeffrey A Robl

doi:10.1016/j.bmcl.2012.10.091

Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists

Bioorg Med Chem Lett. 2013 Jan 1;23(1):330-5. doi: 10.1016/j.bmcl.2012.10.091. Epub 2012 Nov 2.

Authors

John M Fevig¹, Jianxin Feng, Karen A Rossi, Keith J Miller, Ginger Wu, Chen-Pin Hung, Thao Ung, Sarah E Malmstrom, Ge Zhang, William J Keim, Mary Jane Cullen, Kenneth W Rohrbach, Qinling Qu, Jinping Gan, Mary Ann Pelleymounter, Jeffrey A Robl

Affiliation

¹ Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. [email protected]

PMID: 23177783
DOI: 10.1016/j.bmcl.2012.10.091

Abstract

A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.

MeSH terms

Animals
Half-Life
Heterocyclic Compounds, 3-Ring / chemical synthesis*
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacokinetics
Humans
Isoquinolines / chemical synthesis
Isoquinolines / chemistry*
Isoquinolines / pharmacokinetics
Male
Pyrroles / chemical synthesis*
Pyrroles / chemistry*
Pyrroles / pharmacokinetics
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2A / chemistry
Receptor, Serotonin, 5-HT2A / metabolism
Receptor, Serotonin, 5-HT2B / chemistry
Receptor, Serotonin, 5-HT2B / metabolism
Receptor, Serotonin, 5-HT2C / chemistry*
Receptor, Serotonin, 5-HT2C / metabolism
Serotonin 5-HT2 Receptor Agonists / chemical synthesis*
Serotonin 5-HT2 Receptor Agonists / chemistry
Serotonin 5-HT2 Receptor Agonists / pharmacokinetics
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 3-Ring
Isoquinolines
Pyrroles
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists