Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.

Imines and alkenes can be converted into the corresponding aziridines and cyclopropanes (see scheme, PTC=phase‐transfer catalyst, Ts=toluene‐4‐sulfonyl) in good yield with moderate to high d.r. and high ee values using tosylhydrazone salts with catalytic quantities of chiral sulfide (5–20 mol %) and metal catalyst (1 mol %). The process is particularly suited to the synthesis of conformationally locked cyclopropyl amino acids, which can now be prepared in only three steps from commercially available material in 100 % ee.

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 ...

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...