3 research outputs found
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
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates
Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration
The use of β-lactam (BL) and
β-lactamase
inhibitor
combination to overcome BL antibiotic resistance has been validated
through clinically approved drug products. However, unmet medical
needs still exist for the treatment of infections caused by Gram-negative
(GN) bacteria expressing metallo-β-lactamases. Previously, we
reported our effort to discover pan inhibitors of three main families
in this class: IMP, VIM, and NDM. Herein, we describe our work to
improve the GN coverage spectrum in combination with imipenem and
relebactam. This was achieved through structure- and property-based
optimization to tackle the GN cell penetration and efflux challenges.
A significant discovery was made that inhibition of both VIM alleles,
VIM-1 and VIM-2, is essential for broad GN coverage, especially against
VIM-producing P. aeruginosa. In addition, pharmacokinetics
and nonclinical safety profiles were investigated for select compounds.
Key findings from this drug discovery campaign laid the foundation
for further lead optimization toward identification of preclinical
candidates