Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

We have synthesized several C₇-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound <b>6a</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5 nM). We have also synthesized a C_9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (<i>K</i>_i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Spirocyclic Analogues of Vorapaxar

We have synthesized several C₇-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound <b>5c</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series

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 MK-8282 as a Potent G‑Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy

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