Synthesis and biological evaluation of novel hexahydro-pyrido[3′, 2′:4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2C receptor agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 5, 2006, Pages 1207-1211

  Richter, Hans G F ^a   Adams, D R ^b   Benardeau, A ^a   Bickerdike, M J ^b   Bentley, J M ^b,c   Blench, T J ^b   Cliffe, I A ^b   Dourish, C ^b   Hebeisen, P ^a   Kennett, G A ^b   Knight, A R ^b   Malcolm, C S ^b   Mattei, P ^a   Misra, A ^b   Mizrahi, J ^a   Monck, N J T ^b   Plancher, J M ^a   Roever, S ^a   Roffey, J R A ^b   Taylor, S ^a   Vickers, S P ^b   more..

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b Vernalis PLC   (United Kingdom)

^c GSK   (Italy)

Author keywords

5 HT2C receptor agonist; hERG; Obesity; Phospholipidosis; Pyrido 3 ,2 :4,5 pyrrolo 1, 2 a pyrazines

Indexed keywords

1,2,3,4,10,10A HEXAHYDRO 1H PYRAZINO[1,2 A]INDOLE; 2 [(CYCLOPROPYLMETHOXY)METHYL] 5,5A,6,7,8,9 HEXAHYDRO 9 METHYL PYRIDO[3',2':4,5]PYRROLO[1,2 A]PYRAZINE; 5,5A,6,7,8,9 HEXAHYDRO PYRIDO[3',2':4,5]PYRROLO[1,2 A]PYRAZINE; 9 METHYL 5,5A,6,7,8,9 HEXAHYDRO PYRIDO[3',2':4,5]PYRROLO[1,2 A]PYRAZINE; INDOLE DERIVATIVE; POTASSIUM CHANNEL HERG; PYRAZINE DERIVATIVE; SEROTONIN 2A RECEPTOR; SEROTONIN 2B RECEPTOR; SEROTONIN 2C AGONIST; SEROTONIN 2C RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BIOLOGICAL ACTIVITY; CHO CELL; CONTROLLED STUDY; DRUG ANTAGONISM; DRUG EFFICACY; DRUG INHIBITION; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; LIPIDOSIS; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHO CELLS; CRICETINAE; HUMANS; HYDROXYLATION; MOLECULAR STRUCTURE; PHOSPHOLIPIDS; PYRAZINES; PYRROLES; RECEPTOR, SEROTONIN, 5-HT2C; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 31344459084     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.11.083     Document Type: Article

References (19)

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13. N2 reaction was determined by means of chiral HPLC using 2% ethanol in heptane as mobile and Chiralpak-AD as stationary phase. Confirmation of the absolute configuration of the C5a- and C9 carbon was carried out by crystallization and X-ray of (5aR,9R)-2-chloro-9- methyl-5a,6,8,9-tetrahydro-(5H)-pyrido[3′,2′:4,5]pyrrolo[1,2-a] pyrazine-7-carboxylic acid 1,1-dimethylethyl ester, which was synthesized according to Scheme 2. CCDC 288646 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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18. 2C receptor subtype were counted and plated into standard 96-well microtiter plates on the day before testing to give a confluent monolayer. The cells were then loaded with the calcium-sensitive dye, Fluo-3-AM. Unincorporated dye was removed using an automated cell washer to leave a total volume of 100 μL/well of assay buffer (Hanks, balanced salt solution containing 20 mM Hepes and 2.5 mM probenecid). The drug (dissolved in 50 μL of the assay buffer) was added at a rate of 70 μL/s to each well of the FLIPR 96-well plate during fluorescence measurements. The measurements were taken at 1 s intervals and the maximum fluorescent signal was measured (approx 10-15 s after drug addition) and compared with the response produced by 10 μM 5-HT (defined as 100%) to which it was expressed as a percentage response (relative efficacy). Dose-response curves were constructed using Graphpad Prism (Graph Software Inc.).
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