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 (EC₅₀ 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-¹⁸<i>F</i>)‑3-(1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-1-yl)isoquinolin-5-amine ([¹⁸F]-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-¹⁸<i>F</i>)-3-(1<i>H</i>-pyrrolo­[2,3-<i>c</i>]­pyridin-1-yl)­isoquinolin-5-amine, <b>6</b> ([¹⁸F]-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