Design of Potent and Orally Active GPR119 Agonists
for the Treatment of Type II Diabetes
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Abstract
We report herein the design and synthesis
of a series of potent
and selective GPR119 agonists. Our objective was to develop a GPR119
agonist with properties that were suitable for fixed-dose combination
with a DPP4 inhibitor. Starting from a phenoxy analogue (<b>1</b>), medicinal chemistry efforts directed toward reducing half-life
and increasing solubility led to the synthesis of a series of benzyloxy
analogues. Compound <b>28</b> was chosen for further profiling
because of its favorable physicochemical properties and excellent
GPR119 potency across species. This compound exhibited a clean off-target
profile in counterscreens and good <i>in vivo</i> efficacy
in mouse oGTT