4 research outputs found
Design and Synthesis of P2–P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors
A new class of hepatitis
C NS3/4A inhibitors was identified by
introducing a novel spirocyclic
proline–P2 surrogate onto the P2–P4 macrocyclic core
of MK-5172 (grazoprevir). The potency profile of new analogues showed
excellent pan-genotypic activity for most compounds. The potency evaluation
included the most difficult genotype 3a (EC<sub>50</sub> values ≤10
nM) and other key genotype 1b mutants. Molecular modeling was used
to design new target compounds and rationalize our results. A synthetic
approach based on the Julia–Kocienski olefination and macrolactamization
to assemble the P2–P4 macrocyclic core containing the novel
spirocyclic proline–P2 moiety is presented as well
Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with <i>in Vivo</i> Activity in Rodents
GPR120 (FFAR4) is
a fatty acid sensing G protein coupled receptor
(GPCR) that has been identified as a target for possible treatment
of type 2 diabetes. A selective activator of GPR120 containing a chromane
scaffold has been designed, synthesized, and evaluated <i>in
vivo</i>. Results of these efforts suggest that chromane propionic
acid <b>18</b> is a suitable tool molecule for further animal
studies. Compound <b>18</b> is selective over the closely related
target GPR40 (FFAR1), has a clean off-target profile, demonstrates
suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout
GPR120 mouse oGTT studies
Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor
We
have been focused on identifying a structurally different next generation
inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under
regulatory review), which would achieve superior pangenotypic activity
with acceptable safety and pharmacokinetic profile. These efforts
have led to the discovery of a novel class of HCV NS3/4a protease
inhibitors containing a unique spirocyclic-proline structural motif.
The design strategy involved a molecular-modeling based approach,
and the optimization efforts on the series to obtain pan-genotypic
coverage with good exposures on oral dosing. One of the key elements
in this effort was the spirocyclization of the P2 quinoline group,
which rigidified and constrained the binding conformation to provide
a novel core. A second focus of the team was also to improve the activity
against genotype 3a and the key mutant variants of genotype 1b. The
rational application of structural chemistry with molecular modeling
guided the design and optimization of the structure–activity
relationships have resulted in the identification of the clinical
candidate MK-8831 with excellent pan-genotypic activity and safety
profile
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