Discovery of structurally novel, potent and orally efficacious GPR119 agonists

Discovery of structurally novel, potent and orally efficacious GPR119 agonists

Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantl...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2014-05, Vol.24 (10), p.2383-2387
Hauptverfasser: Alper, Phil, Azimioara, Mihai, Cow, Christopher, Mutnick, Daniel, Nikulin, Victor, Michellys, Pierre-Yves, Wang, Zhiliang, Reding, Esther, Paliotti, Michael, Li, Jing, Bao, Dingjiu, Zoll, Jocelyn, Kim, Young, Zimmerman, Matthew, Groessel, Todd, Tuntland, Tove, Joseph, Sean B., McNamara, Peter, Seidel, H. Martin, Epple, Robert
Format: Artikel
Sprache:eng
Schlagworte:
Animals
Diabetes Mellitus, Type 2 - drug therapy
GPCR agonists
GPR119
Humans
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Mice
Mice, Inbred C57BL
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyrazolopyrimidines
Pyrimidines - chemistry
Pyrimidines - pharmacology
Receptors, G-Protein-Coupled - agonists
Structure-Activity Relationship
Type 2 diabetes
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Zusammenfassung:Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.03.023