2 research outputs found
Discovery of MK-8282 as a Potent G‑Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes
The ever-growing prevalence of type
2 diabetes in the world has necessitated an urgent need for multiple
orally effective agents that can regulate glucose homeostasis with
a concurrent reduction in body weight. G-Protein coupled receptor
119 (GPR119) is a GPCR target at which agonists have demonstrated
glucose-dependent insulin secretion and shows beneficial effects on
glycemic control. Herein, we describe our efforts leading to the identification
of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose
tolerance in multiple animal models and has excellent off-target profile.
The key design elements in the compounds involved a combination of
a fluoro-pyrimidine and a conformationally constrained bridged piperidine
to impart good potency and efficacy
Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes
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