Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Wacker DA,
Varnes JG,
Malmstrom SE,
Cao X,
Hung CP,
Ung T,
Wu G,
Zhang G,
Zuvich E,
Thomas MA,
Keim WJ,
Cullen MJ,
Rohrbach KW,
Qu Q,
Narayanan R,
Rossi K,
Janovitz E,
Lehman-McKeeman L,
Malley MF,
Devenny J,
Pelleymounter MA,
Miller KJ,
Robl JA.
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. dean.wacker@bms.com
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
PMID: 17315987 [PubMed - indexed for MEDLINE]