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Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists.

Mihai Azimioara, Phil Alper, Christopher Cow, Daniel Mutnick, Victor Nikulin, Gerald Lelais, John Mecom, Matthew McNeill, Pierre-Yves Michellys, Zhiliang Wang, Esther Reding, Michael Paliotti, Jing Li, Dingjiu Bao, Jocelyn Zoll, Young Kim, Matthew Zimmerman, Todd Groessl, Tove Tuntland, Sean B Joseph, Peter McNamara, H Martin Seidel, Robert Epple
Bioorganic & Medicinal Chemistry Letters 2014 December 2
Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.

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