5 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 Novel Tricyclic Heterocycles as Potent and Selective DPP‑4 Inhibitors for the Treatment of Type 2 Diabetes
In
our efforts to develop second generation DPP-4 inhibitors, we endeavored
to identify distinct structures with long-acting (once weekly) potential.
Taking advantage of X-ray cocrystal structures of sitagliptin and
other DPP-4 inhibitors, such as alogliptin and linagliptin bound to
DPP-4, and aided by molecular modeling, we designed several series
of heterocyclic compounds as initial targets. During their synthesis,
an unexpected chemical transformation provided a novel tricyclic scaffold
that was beyond our original design. Capitalizing on this serendipitous
discovery, we have elaborated this scaffold into a very potent and
selective DPP-4 inhibitor lead series, as highlighted by compound <b>17c</b>
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
The Discovery of <i>N</i>‑((2<i>H</i>‑Tetrazol-5-yl)methyl)-4-((<i>R</i>)‑1-((5<i>r</i>,8<i>R</i>)‑8‑(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): A Potent and Selective Glucagon Receptor Antagonist
A novel
series of spiroimidazolone-based antagonists of the human
glucagon receptor (hGCGR) has been developed. Our efforts have led
to compound <b>1</b>, <i>N</i>-((2<i>H</i>-tetrazol-5-yl)methyl)-4-((<i>R</i>)-1-((5<i>r</i>,8<i>R</i>)-8-(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide
(SCH 900822), a potent hGCGR antagonist with exceptional selectivity
over the human glucagon-like peptide-1 receptor. Oral administration
of <b>1</b> lowered 24 h nonfasting glucose levels in imprinting
control region mice on a high fat diet with diet-induced obesity following
single oral doses of 3 and 10 mg/kg. Furthermore, compound <b>1</b>, when dosed orally, was found to decrease fasting blood glucose
at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse
pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose
excursion in prediabetic mice
Discovery of 6‑(Fluoro-<sup>18</sup><i>F</i>)‑3-(1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-1-yl)isoquinolin-5-amine ([<sup>18</sup>F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)
Neurofibrillary tangles
(NFTs) made up of aggregated tau protein
have been identified as the pathologic hallmark of several neurodegenerative
diseases including Alzheimer’s disease. In vivo detection of
NFTs using PET imaging represents a unique opportunity to develop
a pharmacodynamic tool to accelerate the discovery of new disease
modifying therapeutics targeting tau pathology. Herein, we present
the discovery of 6-(fluoro-<sup>18</sup><i>F</i>)-3-(1<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin-1-yl)isoquinolin-5-amine, <b>6</b> ([<sup>18</sup>F]-MK-6240), as a novel PET tracer for detecting
NFTs. <b>6</b> exhibits high specificity and selectivity for
binding to NFTs, with suitable physicochemical properties and in vivo
pharmacokinetics