The demand for new chemicals spanning the fields of health care to materials science combined with the pressure to produce these substances in an environmentally benign fashion pose great challenges to the synthetic chemical community. The maximization of synthetic efficiency by the conversion of simple building blocks into complex targets remains a fundamental goal. In this context, ruthenium complexes catalyze a number of non-metathesis conversions and allow the rapid assembly of complex molecules with high selectivity and atom economy. These complexes often exhibit unusual reactivity. Careful consideration of the mechanistic underpinnings of the transformations can lead to the design of new reactions and the discovery of new reactivity.

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.C hronic hepatitis C virus (HCV) infection afflicts more than 170 million people worldwide and is the major etiological cause of fibrosis, liver cirrhosis, and hepatocellular carcinoma (20,53). Current treatment relies on a backbone of interferon and ribavirin, a regimen with poor tolerability and toxicity (31, 34). Efforts to develop novel therapies to improve treatment have focused largely on direct acting antiviral agents (DAAs) (19), which therapeutically intervene with virally encoded components essential for HCV replication.Hepatitis C virus, a member of the Flaviviridae family of viruses in the Hepacivirus genus, is encoded by a 9.6-kb positivestrand RNA genome (8). It is initially translated into a single polypeptide that is subsequently cleaved into individual protein components by a combination of both host-and virally encoded proteases (2, 38). HCV protease inhibitors currently in clinical development span a variety of structural classes. The most advanced of these are keto amide compounds, which covalently bind to the active-site serine of the protease in a slowly reversible manner. Boceprevir (29) and telaprevir (37), both from this class, recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin in the treatment of genotype 1-infected patients. A number of rapidly reversible NS3/4a protease inhibitors, including the P1-P3 constrained macrocyclic inhibitors TMC 435 (23) and danoprevir (45), the P2-P4 constrained macrocyclic inhibitor vaniprevir (33), the linear inhibitors BI 201335 (52), BMS650032 (47), and ABT-450 ...

Angiotensin II receptors, AT1R and AT2R, serve as key components of the renin-angiotensin-aldosterone system. While AT1R plays a central role in the regulation of blood pressure, the function of AT2R is enigmatic with a variety of reported effects. To elucidate the mechanisms for the functional diversity and ligand selectivity between these receptors, we report crystal structures of the human AT2R bound to an AT2R-selective and an AT1R/AT2R-dual ligand, respectively, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins/β-arrestins, in agreement with the lack of signaling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the interactions critical for ligand binding and selectivity. Our results thus provide insights into the structural basis for distinct functions of the angiotensin receptors, and may guide the design of novel selective ligands.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1−3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.KEYWORDS: hepatitis C, HCV, MK-5172, macrocycle, genotype 3a, mutant enzymes H epatitis C virus (HCV) is a chronic liver infection that affects an estimated 130−170 million people worldwide. 1,2 HCV displays a high degree of genetic heterogeneity and can be classified into six major genotypes with different geographic distributions: genotypes 1, 2, and 3 account for more than 90% of the infections in the developed world. Treatment for HCV is based on combination therapy with pegylated interferon-α and ribavirin. 3 Sustained viral response is seen in ∼45% of HCV genotype 1-infected patients treated for 48 weeks and in ∼80% of genotype 2-and 3-infected patients treated for 24 weeks. Interferon and ribavirin therapy is also associated with a number of serious side effects, limiting the number of patients who may be treated. 4 There is a compelling medical need for new oral therapeutic agents with improved efficacy and tolerability. Several promising antiviral targets for HCV have emerged, 5 with NS3/4a protease inhibitors showing perhaps the most dramatic antiviral effects. 6 Clinical proof of concept for this mechanism was first achieved with BILN-2061. 7 Other compounds have entered clinical trials, including telaprevir 8 and boceprevir, 9 both of which are now marketed treatments for use in combination with a standard of care. Compounds currently in development include TMC-435 10 and We have disclosed a molecular modeling-derived strategy that led us to design HCV NS3/4a protease inhibitors that contain the P2 to P4 macrocyclic constraint. 12 This design arose from an analysis of the crystal structure of full-length NS3/4A with and without inhibitors docked in the active site. 13 Our strategy coupled with a modular synthetic approach, which relies on a key ring-closing metathesis (RCM) reaction, 14 allowed for the rapid exploration of these molecules and the identification of clinical candidates, vaniprevir (1) 15,16 and MK-1220 (2). 17 Herein, we describe the discovery of a clinical candidate with broad activity across genotypes (gt) and resistant HCV variants. 18,19 With the development of vaniprevir progressing, we set a goal for the ongoing discovery program to be the identification of a second generation NS3/4a protease inhibitor. We wanted to maintain or improve the PK profile seen with our previous compounds and make significant improvements in activity against the gt 3a enz...

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain’s ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.