2 research outputs found
Discovery of <i>N</i>‑[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia
The discovery of novel 4-hydroxy-2-(heterocyclic)Âpyrimidine-5-carboxamide
inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD)
is described. These are potent, selective, orally bioavailable across
several species, and active in stimulating erythropoiesis. Mouse and
rat studies showed hematological changes with elevations of plasma
EPO and circulating reticulocytes following single oral dose administration,
while 4-week q.d. po administration in rat elevated hemoglobin levels.
A major focus of the optimization process was to decrease the long
half-life observed in higher species with early compounds. These efforts
led to the identification of <b>28</b> (MK-8617), which has
advanced to human clinical trials for anemia
Design, Synthesis, and Evaluation of Novel and Selective G‑protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists
Type 2 diabetes mellitus
(T2DM) is an ever increasing worldwide
epidemic, and the identification of safe and effective insulin sensitizers,
absent of weight gain, has been a long-standing goal of diabetes research.
G-protein coupled receptor 120 (GPR120) has recently emerged as a
potential therapeutic target for treating T2DM. Natural occurring,
and more recently, synthetic agonists have been associated with insulin
sensitizing, anti-inflammatory, and fat metabolism effects. Herein
we describe the design, synthesis, and evaluation of a novel spirocyclic
GPR120 agonist series, which culminated in the discovery of potent
and selective agonist <b>14</b>. Furthermore, compound <b>14</b> was evaluated <i>in vivo</i> and demonstrated
acute glucose lowering in an oral glucose tolerance test (oGTT), as
well as improvements in homeostatic measurement assessment of insulin
resistance (HOMA-IR; a surrogate marker for insulin sensitization)
and an increase in glucose infusion rate (GIR) during a hyperinsulinemic
euglycemic clamp in diet-induced obese (DIO) mice