Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives

Pyrrolopyridinones were designed and established as potent constrained analogs of the pyrazole CB-1 receptor antagonist/inverse agonist rimonabant. A representative analog was also demonstrated to cause significant appetite suppression and reduction in body weight gain in rodent models. A series of...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (3), p.673-678
Hauptverfasser: Smith, Roger A., Fathi, Zahra, Brown, Su-Ellen, Choi, Soongyu, Fan, Jianmei, Jenkins, Susan, Kluender, Harold C.E., Konkar, Anish, Lavoie, Rico, Mays, Ronald, Natoli, Jennifer, O’Connor, Stephen J., Ortiz, Astrid A., Podlogar, Brent, Taing, Christy, Tomlinson, Susan, Tritto, Theresa, Zhang, Zhonghua
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Sprache:eng
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Zusammenfassung:Pyrrolopyridinones were designed and established as potent constrained analogs of the pyrazole CB-1 receptor antagonist/inverse agonist rimonabant. A representative analog was also demonstrated to cause significant appetite suppression and reduction in body weight gain in rodent models. A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with K i and K b values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.10.095